Abstract
Lysosomes serve as central degradative hubs in cells, playing critical roles in maintaining protein homeostasis, clearing damaged organelles, and regulating metabolic signaling. Tumor cells heavily rely on lysosomal functions during proliferation, invasion, and drug resistance, a dependency that concurrently endows them with inherent susceptibility to lysosomal membrane permeabilization (LMP). Current cancer therapies rely heavily on surgical resection for early-stage disease, and chemotherapy or radiotherapy for advanced-stage cancers, but these modalities are limited by poor efficacy, severe side effects, and drug resistance. Therefore, targeting LMP to induce lysosome-dependent cell death (LDCD) represents a promising breakthrough. This review systematically summarizes the molecular mechanisms underlying LMP initiation and execution, as well as the regulatory pathways of LDCD modalities, including apoptosis, necroptosis, ferroptosis, pyroptosis, immunogenic cell death, and autophagy-dependent death. It further highlights the dual roles of lysosomes and LDCD in the tumor microenvironment and their core functions in tumor progression. Additionally, we outline classic therapeutic strategies targeting LMP and novel lysosome-targeting technologies, and discuss combination therapy regimens based on lysosomal modulation. These advances provide comprehensive theoretical foundations and new insights for the development of broad-spectrum lysosome centered anticancer drugs.
Keywords: Lysosomal membrane permeabilization, Lysosome-dependent cell death, Neoplasms, Cell death, Targeted therapy
Graphical Abstract
Introduction
Lysosomes are acidified organelles enclosed by a single layer of biological membrane, with a diameter ranging from approximately 0.1 to 1.2 μm. The Vacuolar-type H+ -transporting ATPase (V-ATPase) on their membrane maintains an intraluminal pH of 4.5–5.0 via proton pumping, thereby providing optimal conditions for various hydrolytic enzymes including proteases, nucleases, and lipases. Among these enzymes, the most extensively studied are the cathepsins, which are classified based on the amino acid residue at their active site into serine cathepsins (CTSA and CTSG), cysteine cathepsins (CTSB, CTSC, CTSF, CTSH, CTSK, CTSL, CTSO, CTSS, CTSV, CTSW, and CTSX), and aspartic cathepsins (CTSD and CTSE). The lysosomal membrane is enriched in specific proteins such as lysosomal associated membrane protein 1/2 (LAMP1/2) and the mannose-6-phosphate receptor (M6PR), and its high stability prevents leakage of hydrolytic enzymes into the cytosol that would otherwise cause cellular damage, while the membrane receptors and transporters enable substrate recognition, endocytic trafficking, and functional regulation, positioning the lysosome as a central hub for intracellular degradation and signal transduction. When cells are exposed to external physicochemical stimuli, pharmacological agents, or endogenous stress signals, the structural stability of the lysosomal membrane can be compromised, leading to lysosomal membrane permeabilization (LMP). This loss of membrane integrity results in the leakage of acidic hydrolases into the cytosol, disruption of ion homeostasis, and excessive generation of reactive oxygen species (ROS) [1]. Mild LMP may be resolved through cellular compensatory repair mechanisms, whereas severe LMP causes widespread release of hydrolases that directly degrade critical intracellular proteins and organelles. Concurrently, it activates caspase family proteases, promotes inflammasome assembly, and ultimately triggers cell death modalities including apoptosis and pyroptosis, or induces necrosis via caspaseindependent pathways [2]. Meanwhile, the mammalian target of rapamycin complex 1 (mTORC1) –transcription factor EB (TFEB) signaling pathway is activated to synthesize new lysosomes, replacing functionally depleted ones and thereby maintaining lysosomal homeostasis. Under physiological conditions, mTORC1 localizes on the lysosomal membrane and phosphorylates TFEB, leading to its sequestration in the cytosol by 14-3-3 proteins and preventing its transcriptional activity. Upon induction of LMP, mTORC1 dissociates from the lysosomal membrane, allowing TFEB to be dephosphorylated and translocate into the nucleus. This initiates the transcription of lysosome biogenesis-related genes and promotes autophagosome formation, collectively restoring the dynamic balance of lysosomes in the cell [3].
Currently, cancer treatment relies on a multimodal approach that combines surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. However, drug resistance and target dependency remain major clinical challenges [4]. Tumor cells can activate the autophagylysosome pathway to repair therapy-induced damage, leading to acquired resistance. Furthermore, lysosome‑mediated endocytic degradation regulates the expression of immune checkpoint proteins such as programmed cell death ligand 1 (PD‑L1). Overexpression of PD‑L1 enables tumor cells to achieve immune evasion; however, under the pressure of immunotherapy, they may exploit the lysosomal pathway to degrade PD‑L1, thereby reducing its surface levels and attenuating the response to immune checkpoint blockade [5]. These issues contribute to the lack of durable efficacy in many patients with advanced cancer, underscoring the urgent need for novel therapeutic targets and strategies. Notably, during malignant proliferation and adaptation to the microenvironment, tumor cells undergo remarkable alterations in lysosomal structure and function, distinguishing them from normal cells. Tumor lysosomes are increased in number and size, exhibit altered membrane stability, display upregulated acidic microenvironments and hydrolase activity, and are often redistributed toward the plasma membrane to facilitate invasion, migration, and nutrient acquisition [6, 7]. As a result of this adaptive remodeling, tumor lysosomes exhibit heightened sensitivity to LMP. In contrast to normal cells, tumor lysosomes are more susceptible to membrane rupture upon external stimuli, leading to the release of hydrolases into the cytosol and triggering lysosome-dependent cell death (LDCD). Normal cells, in contrast, can maintain lysosomal homeostasis through compensatory mechanisms and are less susceptible to such lethal events [8]. The structural and functional abnormalities of tumor lysosomes, together with their high sensitivity to LMP, render them promising and specific targets for cancer therapy. Modulating lysosomal function—by inducing selective LMP, inhibiting lysosomal hydrolase activity, or blocking lysosome-mediated signaling pathways—may enable selective killing of tumor cells while sparing normal cells. Furthermore, lysosometargeted strategies can be combined with conventional radiotherapy, chemotherapy, targeted therapy, or immunotherapy to overcome drug resistance, enhance target stability, and activate antitumor immunity, thereby achieving synergistic therapeutic effects.
This review focuses on the mechanisms of LDCD, with particular emphasis on LDCD and bioactive compounds capable of inducing LMP. Compared with traditional cell death pathways such as apoptosis, LDCD engages crosstalk with multiple death modalities and demonstrates unique advantages in overcoming multidrug resistance—a central bottleneck for cancer therapy. These insights provide a new route to overcoming clinical therapeutic resistance and offer a theoretical as well as experimental basis for the design and development of innovative lysosome-targeted antitumor agents.
Mechanisms of lysosome-dependent cell death
LMP represents the core initiating switch that drives the entire LDCD program. Its execution relies on a highly coordinated molecular network that integrates induction cues, executioner pathways, and regulatory checkpoints, all converging to disrupt membrane integrity and commit the cell to death. LMP serves as the pivotal upstream initiator of LDCD, linking upstream stress inputs to downstream executioner pathways. Its progression involves both membrane-damaging triggers and downstream execution machinery that together drive cell death.
LMP: triggering and execution in cell death
LMP: induction mechanisms
LMP is induced by a diverse array of intrinsic and extrinsic stimuli that compromise lysosomal membrane integrity. These include oxidative stress, Ca2+ dysregulation, lysosomal lipid metabolism alterations, and metal ion imbalance, which collectively destabilize membrane proteins and lipids to initiate LMP (Fig. 1A). Intracellular accumulation of ROS serves as a major endogenous inducer of LMP, generated through either endogenous or exogenous pathways. ROS encompass a group of oxygen-derived molecules, including the hydroxyl radical (•OH), peroxyl radical (ROO•), alkoxyl radical (RO•), and hydrogen peroxide (H2O2) [9]. Although ROS are inevitably produced during mitochondrial respiratory chain activity, their levels are normally low. In contrast, mitochondrial dysfunction significantly increases cellular ROS generation [10]. Additionally, DNA damageactivated p53 signaling—which induces expression of genes including p53-induced gene 3 (PIG3) encoding nicotinamide adenine dinucleotide phosphate (NADPH) oxidases—and endoplasmic reticulum stress also contribute to ROS accumulation [11–14]. H2O2 reacts with Fe2+ via Fenton and Fentonlike reactions to generate large amounts of •OH, a highly reactive form of ROS that attacks lipids, proteins, and other biomolecules on the lysosomal membrane. Concurrently, ROS directly activate cytosolic or membranebound phospholipase A2 (PLA2), which catalyzes the hydrolysis of lysosomal membrane phospholipids, yielding metabolites such as arachidonic acid. Further metabolism of these products generates reactive lipid species (e.g., eicosanoids), exacerbating oxidative damage to the lysosomal membrane [15]. Accordingly, the application of antioxidants such as Nacetylcysteine or ironchelating proteins markedly attenuates ROS-induced LMP and reduces cell death [16, 17].
Fig. 1.
Induction of LMP and execution of LDCD. (A) Multiple stress signals converge to trigger LMP. ROS, generated by mitochondrial dysfunction, protein misfolding, radiation, and chemotherapeutic drugs, drive lipid peroxidation and DNA damage, leading to p53 activation and lysosomal injury. Other triggers include calcium overload, autophagy disorders, and sphingolipid/lysosomal protease imbalance. (B) Mechanisms of cell death execution following LMP. Release of cathepsins activates the caspase cascade and disrupts the cytoskeleton. LMP also induces MOMP, promoting Cyto c release and apoptosome formation, which collectively drive cell death. (C) Regulation of LMP. Damaged lysosomes are either repaired by ESCRT-III or cleared via lysophagy. Hsp70 and Bcl-2 stabilize the membrane to inhibit LMP, while pro-apoptotic factors promote LMP, forming a regulatory balance
Ca2+, a key messenger in multiple signaling pathways, directly activates proteases such as calpain upon elevation of its concentration. Activated calpain in turn disrupts lysosomal membrane integrity by cleaving various lysosomal proteins, including LAMP2 and heat shock protein 70 (Hsp70) [18]. Similarly, upregulation of cathepsin expression and activity leads to decreased levels of LAMP1/2, while overexpression of LAMP3 promotes LAMP1 degradation and increases caspase-8 expression. Both events elevate lysosomal membrane permeability, cause relocalization of cathepsins to the cytosol, and subsequently destabilize autophagic flux and activate caspases [19–21]. Moreover, acid sphingomyelinase (ASM) mediated hydrolysis of sphingomyelin to ceramide, followed by the action of acid ceramidase, generates sphingosine. Among these metabolites, sphingosine—but not ceramide—plays a pivotal role in destabilizing lysosomal membranes by acquiring detergent‑like properties upon protonation and accumulation within the lysosomal lumen [22, 23].
Disruption of lysosomal pH homeostasis also represents an important factor contributing to LDCD. Aberrant pH not only impairs the activity of pH-dependent hydrolases but also drives the buildup of non-degraded cargo—such as misfolded proteins and lipids—inside lysosomes [24]. For example, rapidly proliferating T cells generate ammonia through mitochondrial glutaminolysis and sequester it within lysosomes. Excessive ammonia accumulation leads to lysosomal alkalinization and impaired autophagic flux, ultimately triggering T-cell death [25]. Within cells, the aforementioned inducers do not act in isolation; rather, they interact and cooperate to jointly increase lysosomal membrane permeability and drive cell death.
Conversely, cells possess molecular mechanisms that help maintain lysosomal membrane homeostasis. Hsp70 family members localize to distinct intracellular compartments. The major stress-inducible Hsp70 is highly abundant in the cytoplasm and plasma membrane of primary tumors of diverse origins [26]. Within the acidic lumen of lysosomes, Hsp70 binds bis(monoacylglycero)phosphate (BMP) with high affinity, thereby facilitating the association of BMP with ASM and enhancing ASM enzymatic activity [27]. Notably, the increase in ASM activity induced by Hsp70 upregulation promotes local ceramide generation, which in turn alters the spatial conformation of the lysosomal membrane, stabilizes the lysosomal membrane structure, and inhibits LMP triggered by various stimuli, including cytokines, anticancer drugs, γ-irradiation, oxidative stress, and photolysis. As noted earlier, ROS can destabilize the lysosomal membrane. Cells have evolved multiple protective systems to scavenge ROS and mitigate their detrimental effects, including low-molecular-weight antioxidants (e.g., vitamins C and E, coenzyme Q10, and glutathione) and antioxidant enzymes [28]. Additionally, ironchelating proteins and Hsp70 can reduce ROS-induced LMP by attenuating Fentontype reactions [28]. Furthermore, studies have shown that moderate cholesterol accumulation can significantly reduce the incidence of LMP and protect cells from LDCD by inhibiting the release of pro‑apoptotic cathepsins into the cytosol and enhancing the rigidity and stability of the lysosomal membrane [29]. However, when cholesterol accumulates excessively within lysosomes (e.g., in lysosomal storage disorders such as Niemann‑Pick disease), it disrupts the lipid composition and fluidity of the lysosomal membrane, induces lysosomal lipid peroxidation (LLP) and metabolic disturbances, and ultimately promotes LMP and subsequent cell death signaling cascades [30, 31]. Therefore, cholesterol exerts a dose‑dependent dual effect on LMP: within the physiological range or upon mild accumulation, it plays a protective role, whereas pathological overaccumulation becomes detrimental, exacerbating lysosomal dysfunction and cell death.
LMP: execution mechanisms
Upon LMP, enhanced lysosomal membrane permeability results in the release of CTSB, CTSD, CTSL, as well as other cysteine and aspartic proteases into the cytoplasm (Fig. 1B) [32]. Although the neutral cytosolic pH is not ideal for their catalytic function, these hydrolases maintain sufficient proteolytic capacity to initiate programmed cell death [33]. CTSB can activate members of the caspase family, thus initiating the apoptotic program. In contrast, CTSD and CTSL directly degrade structural proteins (e.g., cytoskeletal components) and functional proteins (e.g., signaling molecules) in the cytosol, disrupting intracellular homeostasis and ultimately causing structural collapse of the cell [33–37]. Released cathepsins can also target mitochondria, inducing mitochondrial dysfunction. For instance, they may degrade anti-apoptotic proteins located on the mitochondrial membrane or directly disrupt mitochondrial membrane integrity. This leads to a loss of mitochondrial membrane potential and the opening of the mitochondrial permeability transition pore (MPTP), which subsequently drives the release of pro-apoptotic factors such as cytochrome C (Cyto C) from mitochondria [38]. Cyto C binds to apoptotic protease activating factor 1 (Apaf-1) and caspase-9 to assemble the apoptosome, which further activates downstream caspases and amplifies the apoptotic signal. Concurrently, mitochondrial dysfunction exacerbates the generation of ROS, establishing a “ROS-LMP-mitochondrial damage” positive feedback loop that further accelerates cell death [39]. In addition to the release of proteolytic enzymes, LDCD also features the irregular release of lysosomal ions and small-molecule metabolites. In pathological states, lysosomal membrane damage triggers massive Zn2+ efflux via upregulated transient receptor potential mucolipin 1 (TRPML1) channel (Table 1). This zinc release directly initiates necrotic cell death cascades and exerts an essential function in specific malignancies, including metastatic melanoma [40, 41].
Table 1.
Expression and prognostic value of lysosomal proteins in tumor cells
| Type of Tumor |
Lysosomal Protein |
Type of samples and expression changes | Outcomes | Ref |
|---|---|---|---|---|
| Esophageal Cancer | CTSE | Tissue (↑) |
Barrett’s esophagus >>esophageal adenocarcinoma > normal tissue, but no correlation with survival Serum CTSE failed to distinguish patient cohorts and cannot serve as a biomarker |
[42] |
| Gastric Cancer | CTSB |
Tissue (↑) Serum (↑) |
Serum CTSB: associated with tumor stage, distant metastasis, poor prognosis potential prognostic biomarker |
[43] |
| CTSD | Tissue (↑) |
Associated with lymph node metastasis in GC potential guide for lymph node dissection |
[44] | |
| CTSF |
Tissue (↓) Cell Line (SGC7901, BGC823, NGC803, HGC27, AGS, MKN45) |
Associated with poor differentiation, deep invasion, and lymph node metastasis | [45] | |
| CTSL | Tissue (↑) | Promote tumor angiogenesis and hematogenous metastasis | [46] | |
| LAMP5 | Tissue (↑) | Associated with GC metastasis and poor prognosis, accompanied by aberrant expression of EMT and autophagy-related genes | [47] | |
| LAPTM4B-35 | Tissue (↑) | Associated with GC metastasis and poor prognosis | [48] | |
| Hsp70 | ↑ | Associated with well-differentiated tumors, intestinal-type GC, and lymphatic invasion; not recommended as a prognostic biomarker | [49] | |
| Colorectal Cancer | CTSA |
Tissue (↑) Cell Line (HCT116, LOVO) |
Associated with lymph node metastasis in CRC | [50] |
| CTSB |
Tissue (↑) Serum (↑) |
Associated with CRC stage and poor prognosis Serum detection sensitive and accurate; p otential biomarker |
[51] | |
| CTSC | Cell Line (HCT116, HT29, KM12C) | Activates autophagy and Promote cell proliferation | [52] | |
| CTSD | Serum (↑) | Inhibits LMP‑mediated cell death | [53, 54] | |
| CTSK |
Tissue (↑) Cell Line (MC38) |
Associated with CRC invasion, TAM M2‑like polarization, and poor prognosis | [55] | |
| CTSL |
Tissue (↑); Serum (↑) Cell Line (SW480, SW620, SW1116, SW837, SW948) |
Associated with poor prognosis in CRC | [51, 56] | |
| CTSS |
Tissue (↑) Cell Line (SL4) |
Associated with poor differentiation, tumor stage, metastasis, recurrence, and poor prognosis Associated with TAM M2-like polarization |
[57] | |
| CTSX | Tissue |
Highly expressed in early stage, decreases with tumor progression; Associated with poor prognosis Highly expressed in TAMs, suggesting involvement in antitumor immune response |
[58] | |
| Hepatocellular Carcinoma | CTSC |
Tissue (↑) Cell Line (SK-HEP-1, SMMC-7721, HepG2, MHCC-97 H, Hep3B, PLC/PRF/5) |
Associated with HCC proliferation, metastasis, and poor prognosis | [59] |
| CTSD | Serum (↑) | Correlated with alpha-fetoprotein (AFP) levels | [60] | |
| CTSS | Tissue (↑); Cell Line (MHCC97-H) | Associated with HCC proliferation, metastasis, and chemoresistance | [61] | |
| LAMP2 | Tissue (↑) | Promote proliferation and confers resistance to apoptosis in HCC | [62] | |
| LAPTM4B-35 |
Tissue (↑) Serum (↑) |
Associated with poor differentiation, metastasis, recurrence, chemoresistance, and poor prognosis in HCC Potential biomarker |
[63] | |
| LAPTM5 | Tissue (↑) |
Enhance autophagy and promote lenvatinib resistance in HCC Potential biomarker for predicting lenvatinib sensitivity |
[64] | |
| Hsp70 | Tissue (↑) |
Promote HCC progression Potential biomarker |
[65] | |
| Pancreatic Cancer | CTSB | Tissue (↑) | Associated with tumor invasion | [66] |
| CTSD |
Tissue (↑) Serum (↑) |
Associated with tumor invasion Potential biomarker |
[66, 67] | |
| CTSE | Tissue (↑) | High detection specificity; enables precise tumor localization via non-invasive fluorescence molecular imaging to assist surgical guidance. | [68] | |
| CTSL |
Tissue (↑) Serum (↑) |
Associated with PC invasion and poor prognosis Potential independent prognostic factor |
[69] | |
| Hsp70 | Tissue (↑) | Promote EMT; associated with pancreatic cancer invasiveness and poor prognosis | [70] | |
| V-ATPase | Cell Line (PANC-1, MIA PaCa-2) (↓) | Associated with chemoresistance | [71] | |
| Tissue (↑) | Associated with tumor invasion | [72] | ||
|
Breast Cancer (BC) |
CTSA | Tissue (↑) |
Higher expression in carcinoma with invasive features than in ductal carcinoma in situ (DCIS) Associated with poor prognosis |
[73] |
| CTSB | Tissue (↑) |
Correlated with tumor size, histological grade, and recurrence Independent prognostic factor for node‑negative (N0) patients |
[74] | |
| CTSC | Tissue (↑) | Recruit neutrophil infiltration and Promote NETs formation, leading to BC lung metastasis | [75] | |
| CTSD | Tissue (↑) | Associated with lymph node involvement, cell proliferation, angiogenesis, and metastasis | [74, 76] | |
| CTSE | Serum (↓) |
Associated with poor prognosis Potential independent prognostic biomarker |
[77] | |
| CTSK | Tissue (↑) | Associated with BC bone metastasis | [78] | |
| CTSL | Tissue (↑) | Associated with poor differentiation and tumor stage in TNBC | [74, 79] | |
| CTSS | Cell Line (MDA-MB-231, MCF-7) | Promote TNBC cell proliferation and invasive metastasis | [80] | |
| CTSV/L2 | Tissue (↑) | Associated with poor prognosis in DCIS of the breast | [81] | |
| CTSX | Cell Line (MCF-7) | Promote EMT independent of TGF‑β1 | [82] | |
| V-ATPase | Tissue (↑) | Correlated with tumor invasion and metastasis | [83] | |
| Cervical Cancer | CTSL | Tissue (↑) | Associated with tumor migration, invasion, and adverse prognosis | [84] |
| Hsp70 | Tissue (↑) | Associated with disease progression | [85] | |
|
Ovarian Cancer (OV) |
CTSD | Tissue (↑) |
Associated with OV malignancy High expression in tumor epithelial cells correlates with favorable prognosis |
[86] |
| CTSK | Tissue (↑); Cell Line (OV-2008) | Associated with OV peritoneal metastasis and poor prognosis | [87] | |
| CTSL |
Tissue (↑) Cell Line (SKOV3, SKOV3/TAX) |
Associated with OV aggressiveness and chemoresistance | [88] | |
|
Non-Small Cell Lung Cancer (NSCLC) |
CTSA | Cell Line (A549) (↑) | Promote cell proliferation, migration, and invasion | [89] |
| CTSB | Tissue (↑) | Associated with lung cancer recurrence and reduced overall survival | [90] | |
| CTSK | Tissue (↑) | Associated with lung cancer recurrence and reduced overall survival | [90] | |
| CTSL | Cell Line (A549, H1299) | Induce EMT and mediates chemoresistance | [91] | |
| CTSS | Serum (↑) | Promote basement membrane degradation and induces invasion | [92] | |
| ASM |
Tissue (↑) Serum (↑) |
Associated with immune evasion | [93] | |
| Melanoma | CTSB | Serum (↑) |
Associated with melanoma metastasis and shorter overall survival Potential prognostic factor for advanced disease |
[94] |
| CTSD | Tissue (↑) | May be associated with tumor development and progression | [95] | |
| CTSH | Serum (↑) |
Associated with shorter overall survival in melanoma Potential prognostic factor for advanced disease |
[94] | |
| CTSK | Tissue (↑) | Correlated with melanoma metastasis and adverse prognosis | [96] | |
| TRPML1 | Tissue (↑) | Associated with poor prognosis, increased lysosomal biogenesis | [40] | |
| Glioma | CTSB | Tissue (↑) |
Associated with glioma invasion, poor differentiation, and shorter survival Potential prognostic factor for glioblastoma |
[97] |
| CTSD | Tissue (↑) | Enhance autophagy leading to radioresistance and associated with invasiveness | [97] | |
| CTSH | Tissue (↑) | Associated with glioma dedifferentiation and disease progression | [98] | |
| CTSK | Tissue (↑) | No statistically significant correlation with glioblastoma survival | [99] | |
| CTSL | Tissue (↑) | Promote glioma dedifferentiation, angiogenesis, and radioresistance | [100] | |
| CTSX | Tissue (↑) | Associated with glioblastoma invasiveness and angiogenesis | [99] | |
| Renal Cell Carcinoma | CTSC | Cell Line (786-O, A-498) (↑) | Associated with tumor migration and invasion | [101] |
| CTSF | Tissue (↓) |
Associated with poor prognosis in RCC Potential diagnostic and prognostic biomarker |
[102] | |
| LAMP1 | Tissue (↓) |
Associated with proliferation, migration, and invasion in clear cell RCC Potential diagnostic and prognostic biomarker |
[103] | |
| LAPTM5 | Tissue (↑) |
Associated with poor differentiation and poor prognosis in RCC Potential biomarker for overall survival in clear cell RCC |
[104] | |
| Bladder Cancer | CTSD | Tissue (↑) | No predictive value for biological behavior | [105] |
| CTSE | Tissue |
High expression correlates with longer progression‑free survival Potential independent prognostic factor for bladder cancer |
[106] | |
| CTSF | Tissue (↓) |
Correlated with bladder cancer proliferation Promote CD8+ T cell exhaustion |
[107] | |
| CTSH | Tissue (↑) | Correlated with cisplatin resistance and basaloid/squamous differentiation | [108] | |
| LAPTM5 | Tissue (↑) | Correlated with bladder cancer motility and invasiveness | [109] | |
| Prostate Cancer | CTSA |
Tissue (↑) Cell Line (PC3, DU145) (↑) |
Promote EMT and tumor progression | [110] |
| CTSB | Cell Line (PC3, DU145) (↑) | Correlated with prostate cancer motility and invasiveness | [111] | |
| CTSH | Cell Line (PC3) | Promote migratory and invasive capacity through cleavage of the cytoskeletal protein Talin | [112] | |
| CTSK |
Tissue (↑) Cell Line (LNCaP, C4-2B, PC3) (↑) |
Associated with prostate cancer invasion and bone metastasis | [113] | |
| CTSS | Tissue (↑) | Abundantly elevated in castration-resistant, poorly differentiated, or high-Gleason grade tumors | [114] | |
| CTSX | Tissue (↑) | May be associated with early prostate cancer progression | [115] | |
| CTSZ | Tissue (↑) | Associated with higher Gleason score, advanced T/N stage, and poor prognosis | [116] | |
| Myeloid Leukemia | CTSB |
Patient Samples (↑) Cell Line (HL-60) (↑) |
Associated with poor prognosis in AML | [117] |
| CTSD | Patient Samples (↑) | Associated with AML disease progression and poor prognosis | [36] | |
| CTSG | Patient Samples (↑) |
Associated with poor prognosis in AML Potential immunotherapy target |
[118] | |
| TRPML1 | Cell Line (OCI-AML3, HL-60, K562, THP1) (↑) | Associated with chemoresistance in AML | [119] | |
| Lymphocytic Leukemia | SPP1 | Patient Samples (↑) | Sensitive to LDCD | [120] |
| CTSG | Patient Samples (↑) | Associated with poor prognosis in ALL | [121] | |
| Lymphoma | CTSL |
Patient Samples (↑) Cell Line (Jurkat, Hut 78) (↑) |
May mediate anti-apoptotic effects in peripheral T-cell lymphoma via the p53 signaling pathway | [122] |
| CTSS | Patient Samples (↑) | Associated with the immunosuppressive microenvironment in follicular lymphoma | [123] |
LDCD: regulatory networks
In numerous malignancies, aberrant overexpression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) family members or reduced expression of pro-apoptotic Bcl-2-related proteins is frequently detected, both of which suppress cell death [124, 125]. For instance, upon cleavage by caspase-8, BH3-interacting domain death agonist (Bid) translocates to the lysosomal membrane and binds to phosphatidic acid, thereby disrupting membrane integrity. Concurrently, Bcl-2-associated X protein (BAX) and Bcl-2 homologous antagonist/killer (BAK) can form pores directly in the lysosomal membrane, increasing its permeability. These proteins also induce mitochondrial outer membrane permeabilization (MOMP), resulting in the release of caspase-activating factors and other mediators of cell death [125–128]. Antiapoptotic proteins (e.g., Bcl-2) maintain membrane integrity by binding to BAX and BAK, thereby preventing their activation (Fig. 1C) [125]. Under cellular stress conditions, such as DNA damage or nutrient deprivation, specific signaling pathways are activated to positively regulate LMP. The p53 protein, for example, transcriptionally upregulates genes including p53 up-regulated modulator of apoptosis (PUMA) and Phorl-12-myristate-13-acetate-induced protein 1 (NOXA), thereby enhancing the expression of pro-apoptotic proteins and facilitating LMP. Additionally, Activated c-Jun N-terminal kinase (JNK) elicits phosphorylation of lysosomal membrane proteins, disrupting membrane integrity and promoting LMP [14, 129].
In response to LMP, multiple proteins act in concert to exert protective functions and maintain cellular homeostasis. Anti-apoptotic Bcl-2 family members, including Bcl-2, counter LMP through a dual mechanism: they specifically sequester pro-apoptotic proteins to block their damaging effects on the lysosomal membrane, while also directly anchoring to the lysosomal membrane to enhance its structural stability, thereby reducing the likelihood of LMP [130]. Hsps employ a distinct strategy by binding to lysosomal membrane proteins or cathepsins, thereby precisely inhibiting hydrolase activity and blocking LDCD [27]. Following LMP, Ca2+ release rapidly recruits the apoptosis-linked gene 2 (ALG-2)/ALG-2-interacting protein X (ALIX)–tumor susceptibility gene 101 (TSG101)–endosomal sorting complexes required for transport III (ESCRT-III) complex to the damaged lysosomal membrane. This complex mediates membrane budding and remodeling, facilitating repair and resealing through the release of vesicles into the extracellular milieu. Notably, components of ESCRT-III including charged multivesicular body protein 4B (CHMP4B) have been implicated in tumor progression [131, 132]. However, even in the absence of the ESCRT machinery, lysosomal damage can be rapidly repaired, indicating the existence of alternative repair pathways. These ESCRT-independent mechanisms encompass at least three sub-pathways: one involving scramblase/nSMase-2, another mediated by TRPML1-dependent endoplasmic reticulum (ER) -lysosome contact sites, and a third driven by Myoferlin overexpression [133–136]. When LMP-induced damage exceeds the repair capacity, cells activate lysophagy to mitigate cellular injury. Galectin-3 binds to TRIM16 to terminate ESCRT-mediated repair and instead promotes the ubiquitination of damaged lysosomes, recruiting autophagy-related proteins including microtubule-associated proteins 1A/1B light chain 3 (LC3) to form autophagosomes, thereby suppressing LMP-driven cell death [137, 138].
LMP: signaling pathways and cell death mechanisms
The Recommendations of the Nomenclature Committee on Cell Death 2018 classify cell death into two primary categories: accidental cell death (ACD) and regulated cell death (RCD) [139]. Of particular significance, LMP serves as an upstream core event through which cells perceive stress signals, playing a pivotal role within the regulatory network of cell death. LMP not only exhibits molecular crosstalk with multiple RCD subtypes but can also selectively activate distinct cell death pathways depending on its magnitude and context (Fig. 2). Building upon this central interplay, the following section will provide a detailed dissection of stress-driven RCD closely associated with LMP, aiming to elucidate its molecular mechanisms and regulatory features.
Fig. 2.
LMP regulates multiple types of cell death. LMP acts upstream and is involved in multiple forms of cell death, including apoptosis, regulated necrosis, pyroptosis, autophagic cell death, immunogenic cell death, and ferroptosis
LMP-Associated apoptosis
Under mild LMP, the released CTSB can directly activate caspase-3 and caspase-9 (Fig. 3A), or relieve caspase inhibition by degrading anti-apoptotic proteins, thereby initiating the apoptotic cascade [33]. This process is primarily executed via two molecular axes. The first axis cathepsin-mediated cleavage of Bid, generating its truncated form, t-Bid [140]. Then, t-Bid subsequently translocates to the outer mitochondrial membrane and promotes MOMP. This event facilitates Cyto C release, apoptosome assembly, and further amplification of apoptotic signals through caspase activation [39, 141]. The second axis enables cathepsins to directly modulate apoptosis regulators. These proteases can degrade anti-apoptotic proteins including Bcl-2 and X-linked inhibitor of apoptosis protein, stimulate proapoptotic factors such as BAX, or even bypass apoptosome formation by directly cleaving procaspase-3 [140].
Fig. 3.
The multifaceted role of LMP in regulating cell death pathways. (A) Apoptosis is executed via LMP-dependent release of cathepsins and subsequent activation of caspases. (B) LMP promotes necroptosis through the induction of mitochondrial dysfunction and activation of the RIPK1/RIPK3/MLKL pathway. (C) Pyroptosis is triggered by LMP-mediated ROS production and cathepsin release, leading to NLRP3 inflammasome activation and GSDMD/GSDME cleavage. (D) Ferroptosis is driven by LMP-induced iron overload, lipid peroxidation, and the degradation of GPX4 via ferritinophagy and clockophagy. (E) Immunogenic cell death is induced by LMP, resulting in the release of DAMPs. (F) Autophagy-dependent cell death is characterized by LMP-induced accumulation of autophagosomes and TFEB activation
Under these conditions, the limited release of hydrolases is insufficient to cause severe structural damage to the cell. Consequently, the cell preferentially activates the apoptotic program to preserve tissue homeostasis.
LMP-Associated necroptosis
Severe LMP results in the massive release of cathepsins, which directly degrade cytosolic and nuclear proteins, leading to structural collapse of the cell (Fig. 3B). Upon stimulation, BAX and phosphorylated Mixed Lineage Kinase Domain-Like Protein (MLKL) translocate to the lysosomal membrane, where BAX targets the outer membrane and p-MLKL interacts with the inner lipid bilayer, jointly altering lysosomal membrane architecture and permeability [128]. Phosphorylated MLKL elevates intracellular Ca2+ levels and activates Ca2+ dependent enzymes. Simultaneously, p-MLKL oligomerization promotes lysosomal clustering and fusion, further driving LMP and the release of cathepsins. The quantity of released cathepsins overwhelms the neutralizing capacity of cytosolic protease inhibitors such as cystatins and serpins [142, 143]. Concurrently, substantial proton efflux from these enlarged lysosomes may induce cytoplasmic acidification, thereby enhancing cathepsin activity. Released CTSB and activated calpain cleave Hsp70, further destabilizing remaining lysosomes and exacerbating membrane damage. This cascade culminates in uncontrolled proteolytic activity and ultimately triggers necroptosis [18].
Moreover, LMP-induced mitochondrial injury amplifies ROS generation, which in turn potentiates activation of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)/receptor-interacting serine/threonine-protein kinase 3 (RIPK3) complex and promotes the progression of necroptosis [144]. Morphologically resembling ACD, necroptosis is nevertheless under precise molecular regulation and serves important roles in pathologies such as cancer and ischemia-reperfusion injury [145, 146]. It should be noted that the dependence of necroptosis on cathepsins varies by cell type and stimulus. For instance, McComb et al. demonstrated that CTSB and CTSS can cleave RIPK1, thereby restricting necroptosis in macrophages [147]. Conversely, in tumor necrosis factor (TNF) sensitive L929Ts mouse immortalized fibroblast cells, neither the CTSB inhibitor CA-074Me, the CTSL inhibitor zFF-fmk, nor a broad-spectrum cathepsin inhibitor conferred protection against TNF-induced necroptosis [148, 149].
LMP-Associated ferroptosis
Lysosomes, as intracellular organelles rich in catalytically active Fe2+, participate in the modulation of ferroptosis through multiple pathways, such as iron homeostasis, antioxidant systems, and circadian autophagy. LMP serves as a pivotal trigger initiating these regulatory processes (Fig. 3C).
In terms of iron homeostasis, lysosomes influence cellular iron levels via two principal mechanisms. On one hand, intracellular iron homeostasis is maintained through ferritin storage and release. Nuclear receptor coactivator 4 (NCOA4)‑mediated ferritinophagy and Sequestosome 1 (SQSTM1/p62) dependent autophagic degradation of solute carrier family 40 member 1 (SLC40A1/FPN1) lead to intracellular Fe2+ accumulation, promoting lipid ROS generation via Fenton reactions or activation of lipoxygenase (LOX) family enzymes (e.g., ALOX12, ALOX15) [150–152]. Conversely, knockdown of NCOA4 inhibits ferritinophagy, reducing intracellular free Fe2+ levels and lipid ROS accumulation, thereby suppressing ferroptosis [151]. On the other hand, LMP directly disrupts the lysosome’s regulatory capacity over iron uptake, storage, and transport. In the transferrin (TF)‑transferrin receptor 1 (TFR1) mediated endocytic pathway, Fe3+ is reduced to Fe2+ by Metalloreductase STEAP3 and normally stored or distributed by lysosomes. However, treatment with siramesine alone or in combination with lapatinib induces lysosomal alkalinization and exacerbates LMP, impairing iron trafficking. This dysregulation is accompanied by upregulated TFR1 expression and downregulated FPN1 expression, collectively exacerbating intracellular iron overload and promoting ferroptosis [153, 154]. Lysosomes also compromise antioxidant capacity by promoting chaperone‑mediated autophagy (CMA). This process, dependent on LAMP‑2A, mediates the degradation of glutathione peroxidase 4 (GPX4)—a key enzyme responsible for suppressing lipid peroxidation. Upon ferroptosis induction, CMA activation upregulates LAMP‑2A levels, accelerating GPX4 degradation and impairing the clearance of lipid hydroperoxides, thereby significantly enhancing ferroptosis sensitivity [155]. Furthermore, when clockophagy is triggered, lysosomes selectively degrade aryl hydrocarbon receptor nuclear translocator-like, leading to upregulated expression of Egl-9 family hypoxia-inducible factor 2 (EGLN2). EGLN2 subsequently destabilizes the pro‑survival factor hypoxia‑inducible factor 1α (HIF-1α), ultimately promoting lipid peroxidation and ferroptosis. These mechanisms reveal a novel regulatory axis through which lysosomes participate in ferroptosis via the circadian pathway [156].
More critically, CTSB released following LMP directly mediates ferroptotic signaling. Upon translocation into the nucleus, cytosolic CTSB induces DNA damage and activates stimulator of interferon genes protein 1 dependent ferroptosis. Additionally, CTSB functions as a histone H3‑specific protease, directly triggering ferroptosis through H3 cleavage [157, 158]. Treatment with lysosomal inhibitors (e.g., bafilomycin A1, CA‑074Me), LMP blockers, or cathepsin knockdown significantly suppresses erastin‑induced ferroptosis, further confirming that LMP and subsequent release of lysosomal proteases constitute an essential execution phase in ferroptosis [157, 158].
LMP-Associated pyroptosis
Pyroptosis represents a lytic type of programmed cell death, defined by inflammasome activation and gasdermin-driven plasma membrane pore generation. LMP acts as a pivotal upstream event during the initiation and signal amplification of pyroptotic signaling (Fig. 3D) [146, 159].
On one hand, LMP leads to aberrant elevation of cytosolic Ca2+ concentration, which activates the Ca2+/calmodulin-dependent protein kinase II (CaMKII)–transforming growth factor-β-activated kinase 1 (TAK1)–JNK signaling cascade, promoting phosphorylation and oligomerization of the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC). ASC oligomerization is a core step in NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome assembly (forming the NLRP3–ASC–caspase-1 complex) and its full activation [160]. Simultaneously, cathepsins released upon LMP—primarily CTSB, with contributions from CTSD, CTSL, and CTSX—act synergistically with elevated intracellular ROS levels and K+ efflux to trigger NLRP3 inflammasome assembly and drive caspase-1 activation. Activated caspase-1 subsequently mediates translocation of the Gasdermin D N-terminal (GSDMD-N) fragment to the plasma membrane, leading to pore formation, while promoting maturation and release of interleukin-1β (IL-1β) and interleukin-18 (IL-18), ultimately triggering canonical pyroptosis [161–163]. During cancer chemotherapy, chemotherapeutic agents can induce myeloidderived suppressor cells (MDSCs) to release CTSB via LMP, thereby promoting IL-1β secretion. This cytokine induces CD4+ T cells to secrete IL-17, ultimately compromising the therapeutic efficacy of chemotherapy [164].
On the other hand, LMP prevents endocytosed lipopolysaccharide (LPS) from lysosomal degradation, allowing non-degraded LPS to enter the cytosol and activate caspase-4/5, thereby initiating the noncanonical inflammasome pathway [165, 166]. Excessively accumulated intracellular ROS can reciprocally induce LMP, leading to release of CTSB and CTSD, which further activate caspase-3. Activated caspase-3 cleaves Gasdermin E (GSDME) at specific sites, releasing the membraneperforating GSDME-N terminal fragment. This fragment disrupts osmotic balance and membrane integrity, ultimately triggering GSDME-dependent pyroptosis [16].
Furthermore, LMP can be pharmacologically modulated using lysosomal inhibitors such as bafilomycin A1, which effectively blocks pyroptosis progression. This underscores the central and multifaceted role of LMP in regulating pyroptosis [167].
LMP-Associated immunogenic cell death
LMP triggers immunogenic cell death (ICD) through inducing lysosomal dysfunction and activating immune-related signaling cascades, positioning it as a critical target in cancer immunotherapy (Fig. 3E) [30, 31, 168]. ICD represents a specialized form of cell death characterized by the release of damage-associated molecular patterns (DAMPs), including calreticulin (CALR), ATP, Hsp70/90, and high mobility group box 1 (HMGB1). These molecules collectively elicit a targeted immune response against tumor antigens [169]. LMP triggers the release of hydrolases—among them CTSD—into the cytosol, which in turn activates caspase-8. Activated caspase8 consequently cleaves B-cell receptor-associated protein 31 (BAP31) and Bid, initiating BAX/BAK mediated MOMP. The degree of LMP directly dictates the pattern of cell death and its immunogenic potential. Partial LMP tends to induce apoptosisassociated ICD, whereas complete membrane rupture results in necrosis; only a specific degree of membrane permeabilization effectively activates immune responses [170]. Lysosomal membrane proteins play regulatory roles in this process: LAMP1/2 and Hsp70 stabilize membrane structure and suppress LMP, and their downregulation enhances tumor cell susceptibility to LMP [19, 27]. In glioblastoma and pancreatic cancer models, Hsp70 antagonists disrupt lysosomal membrane stability to induce LMP and demonstrate ICD-inducing activity [171]. Anthracyclines induce ICD and elicit longterm antitumor immunity in various tumor models by activating the p53–ROS–LMP pathway through DNA damage [172]. Furthermore, lysosomal cholesterol accumulation has emerged as an independent trigger of LMP and ICD [30, 31]. Aberrant intralysosomal cholesterol storage destabilizes the limiting membrane, promotes lipid peroxidation, and facilitates the release of lysosomal content into the cytosol, thereby activating DAMP emission. Importantly, cholesterol-overloaded cancer cells exhibit surface exposure of CALR, secretion of ATP, and release of HMGB1, collectively driving dendritic cell (DC) maturation and T-cell priming. This cholesterol-driven LMP does not rely on classical apoptosis or necroptosis machineries but operates through a distinct lysosome-centric pathway.
However, certain tumors develop resistance through upregulation of lysosomal membrane proteins or activation of autophagic repair mechanisms. Future research endeavors should center on elucidating the molecular regulatory networks governing LMP, as well as designing therapeutic agents that precisely target tumor cell lysosomes. The combination of ICD inducers and immune checkpoint inhibitors holds great potential as a promising therapeutic approach to enhance the efficacy of cancer immunotherapy [173, 174].
LMP-Mediated autophagy-dependent cell death
Under stress signals, impairment of lysosomal membrane integrity results in the release of luminal effector molecules, which ultimately triggers autophagy‑dependent cell death by modulating autophagy pathway activation, functional remodeling, or aberrant autophagic flux (Fig. 3F). The functional integrity of core autophagy components is a prerequisite for this mode of cell death [175]. Acid hydrolases released during LMP disrupt the autophagosome‑lysosome fusion machinery, resulting in autophagosome accumulation and the release of toxic substances such as ROS, ultimately depleting cellular metabolic resources [176]. Furthermore, cathepsin‑mediated autophagy reprogramming promotes autophagy by cleaving Bcl‑2 to relieve its inhibition of Beclin‑1 or by activating the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, establishing a “LMP–hyperactivated autophagy” cascade that leads to sustained degradation of essential cellular components [38, 177]. While basal autophagy maintains cellular homeostasis by clearing damaged mitochondria and DNA, sustained stress (e.g., targeted therapy, nutrient deprivation) in cancer cells can lead to excessive activation of the lysosome‑mediated autophagy pathway. This may cause the accumulation of substances such as sphingosine within lysosomes, thereby reducing membrane stability [178]. Under these conditions, LMP on one hand triggers ferritinophagy, releasing free iron that generates ROS—both amplifying LMP damage and activating autophagic pathways. On the other hand, ROS activate the 5’-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, which subsequently phosphorylates unc-51 like autophagy activating kinase 1 (ULK1) (a key autophagy initiator) to promote autophagy, ultimately resulting in autophagy‑dependent ferroptosis [179, 180]. Currently, key questions remain regarding the precise regulatory nodes between LMP and the autophagy pathway, as well as their functional divergence across different disease contexts. Addressing these questions will provide critical theoretical support for developing therapeutic strategies targeting this cell death modality.
Lysosomal characteristics in the tumor microenvironment
In the complex pathological progression of cancer, lysosomes have evolved from their traditional perception as “cellular digestive compartments” into critical regulatory hubs. Their functional dysregulation directly impacts tumor initiation, progression, and therapeutic response [181]. Notably, lysosomal functions in tumor cells do not operate in isolation but are tightly integrated with stromal and immune cells within the tumor microenvironment (TME). This intercellular lysosomal regulatory network constitutes a pivotal mechanism underlying the tumor-promoting actions of the TME.
Functional reprogramming of lysosomes in tumor cells
Aberrant expression of lysosome-related proteins in tumor cells
Lysosomes in tumor cells exhibit notable alterations in number, morphology, and protein composition. Notably, numerous lysosome-related proteins are abnormally expressed in diverse cancers and exhibit a close association with tumor progression as well as patient prognosis (Table 1).
Cathepsins, the most important class of proteases within lysosomes, are highly dependent on an acidic environment for their activity. The predominantly glycolytic metabolism of tumor cells, accompanied by substantial lactate production, provides a favorable condition for cathepsin function [97]. CTSB promotes cell detachment and migration by activating growth factors and matrix metalloproteinases (MMPs). It is highly expressed in the serum of patients with gastric cancer (GC), colorectal cancer (CRC), and melanoma, and correlates with tumor invasion, advanced stage, and poor prognosis [43, 53, 94, 97]. CTSD is produced and abundantly secreted by mammary epithelial cells, promotes fibroblast proliferation through activation of the LDL receptor-related protein 1 receptor, and accelerates endothelial cell proliferation and migration via the ERK-protein kinase B (AKT) pathway [76]. In GC, nuclear‑localized CTSL promotes angiogenesis by activating transcription of vascular endothelial growth factor D (VEGF‑D), a secreted glycoprotein that drives both lymphangiogenesis and angiogenesis, thereby facilitating tumor growth, invasion, and metastasis and is associated with poor patient prognosis. [46]. CTSK has been reported to be highly correlated with bone metastasis; it is highly expressed in both osteolytic lesions of breast cancer and osteoblastic lesions of prostate cancer [78, 113]. Notably, cathepsin expression is not uniformly elevated in tumors. CTSF is downregulated in GC specimens and cell lines, where reduced expression is linked to poor differentiation and enhanced lymph node metastasis potential [45].
LAMP exhibits marked expression heterogeneity across different tumors: it is overexpressed in gastrointestinal tumors, promoting malignant progression, but downregulated in renal cell carcinoma (RCC). As mentioned, Hsp70 serves as an important membraneprotective factor and is upregulated in GC, hepatocellular carcinoma (HCC), pancreatic cancer (PC), and cervical cancer, consistent with enhanced lysosomal function in tumors [49, 65, 70, 85]. In HCC, Hsp70 binds to signal transducer and activator of transcription 3 (STAT3) and regulates the myeloid cell leukemia-1 (MCL1) and AKT pathways, mediating apoptosis resistance and cell migration [65] Similarly, high Hsp70 expression in pancreatic cancer activates the NFκB pathway to promote epithelial-mesenchymal transition (EMT), while simultaneously inhibiting mitochondrial swelling and Beclin1 phosphorylation, thereby attenuating apoptosis [70]. V-ATPase maintains lysosomal acidity to meet the high autophagic demand of tumors. Downregulation of V-ATPase function can inhibit ferritinophagy and mediate ferroptosis in pancreatic cancer, whereas its high expression in breast cancer enhances lysosomal activity and promotes invasion and metastasis [72, 83].
Pro-tumor functions of aberrant lysosomal expression in tumor cells
The aberrant expression profile of lysosomal proteins described above (Table 1) is not merely a set of molecular markers, but rather confers multiple protumor functions upon lysosomes, which protect tumor cells through three key pathways (Fig. 4A). First, in terms of “metabolic support”, the autophagy‑lysosome pathway sustains cancer cell proliferation by modulating mitogenic signaling and metabolic substrates. Growth‑factor signaling, triggered at the cytoplasmic membrane by receptor tyrosine kinases (RTKs) including epidermal growth factor receptor (EGFR), is limited by endolysosomal degradation [182]. To satisfy the elevated energy requirements of cancer cell proliferation and invasion, lysosomes enhance acidic hydrolase activity and autophagy, efficiently degrading aged organelles, misfolded proteins, and extracellular macromolecules. This process generates small‑molecule metabolites (e.g., amino acids, fatty acids) that serve as essential building blocks and energy sources for tumor biosynthesis [183]. When mTORC1 is inactivated, the degradation of endocytosed extracellular proteins via macropinocytosis replenishes nutrients and provides amino acids for tumor cells; consequently, inhibition of both autophagy and macropinocytosis impedes tumor growth [184, 185]. In kirsten rat sarcoma oncogene (KRAS) driven NSCLC and pancreatic ductal adenocarcinoma (PDAC) cells, lysosomes catabolize both extracellularly engulfed material and intracellular autophagic substrates, providing critical metabolic fuel. This metabolic rewiring maintains cellular energy homeostasis, prevents excessive adenosine monophosphate(AMP) accumulation, thereby averting metabolic crisis and suppressing lethal nucleotide degradation pathways [186, 187].
Fig. 4.
The role of lysosomes in sculpting the TME. (A) Tumor cells rewire lysosomal function to drive malignant progression. Lysosomal biogenesis is promoted via the mTOR-TFEB axis, facilitating lysosomal degradation of extracellular proteins and supporting cancer cell proliferation. Additionally, lysosomal acidification and autophagy mediate drug resistance by sequestering chemotherapeutic drugs and inhibiting apoptosis. Lysosomal cathepsins (CTSB/CTSL) facilitate ECM degradation and EMT, thereby promoting tumor invasion and metastasis. The lysosomal network also contributes to tumor immune escape by regulating MHC-I surface expression, PD-L1, and CMTM6. (B) TAMs undergo lysosomal regulation to modulate anti-tumor immunity. Acidic TME and lactic acid activate the mTOR-TFEB pathway in TAMs, downregulating ATP6V0d2 and TRPML1 to drive M2-like polarization. This process stabilizes HIF-2α and activates p38/NF-κB signaling, ultimately leading to ferroptosis evasion and ECM degradation. (C) Lysosomal function in the tumor microenvironment critically regulates T cell activity. Loss of key autophagy genes enhances the cytotoxic potential of CD8+ T cells. Hyperkalemia-induced autophagy suppresses their effector function but mitigates T cell exhaustion. Furthermore, autophagy deficiency in Treg cells inhibits tumor growth. (D) CAFs rely on lysosomal activity to maintain stemness and promote stromal remodeling. CAFs secrete MMPs to degrade ECM, induce angiogenesis via VEGF-A, and sustain an inflammatory TME through IL-6 and CCL2 secretion, collectively supporting tumor maintenance and progression
Second, regarding “invasion and metastasis”, lysosomes are frequently redistributed from the perinuclear region to the cell periphery [188]. Both tumor and stromal cells secrete hydrolases—such as CTSB, CTSL, and MMPs—into the TME. These enzymes specifically degrade extracellular matrix (ECM) components, breaking down tissue barriers and facilitating tumor cell detachment, local invasion, and hematogenous dissemination [189]. As summarized in Table 1, elevated cathepsin expression is common in tumors, though the functional roles of individual cathepsins may vary [190]. Beyond ECM degradation, CTSB and CTSX in several tumor cell lines can stimulate EMT, resulting in loss of polarity and increased migratory and invasive capacities [82]. However, cathepsin expression is not uniformly upregulated across all tumors; depending on the TME, cellular origin, and metabolic context, cathepsins may exhibit opposing functions. For instance, CTSX is upregulated in early‑stage colorectal cancer, but its downregulation correlates with advanced invasion and poorer patient survival [58].
Third, tumor cells exploit the “drug‑sequestration” capacity” of lysosomes to evade therapy. Lipophilic weak‑base chemotherapeutic agents (e.g., cisplatin, doxorubicin, vincristine) passively diffuse across the lysosomal membrane and become protonated and sequestered within the acidic lumen (pH = 4.5–5.0), owing to the substantial pH gradient relative to the cytosol (pH = 7.0–7.5) [191]. Moreover, cancer cells can upregulate lysosomal membrane drug‑transport proteins including P‑glycoprotein (P‑gp), an ATP‑driven efflux pump that actively shuttles cytotoxic drugs into lysosomes. This not only reduces drug availability at intracellular targets but also lowers lysosomal acidity and activity [4]. To compensate for diminished lysosomal function, cells activate TFEB‑mediated lysosomal biogenesis, inducing lysosomal biogenesis and further enhancing drug sequestration and chemoresistance [192]. Although most studies emphasize the key function of lysosomes as mediators of chemoresistance, latest work calls for a more nuanced interpretation of this paradigm [193]. Lysosomes also contribute to therapy tolerance by clearing treatment‑induced toxic agents (e.g., ROS, DNA‑damage fragments) via autophagy, thereby blunting therapeutic efficacy [194]. In the setting of immunotherapy, cancer cells often evade immune recognition through downregulation or blockade of co‑stimulatory molecules. Lysosomes contribute to the breakdown of antigen‑processing machinery and major histocompatibility complex class I (MHC-I) molecules. Autophagy‑dependent lysosomal degradation of MHC‑I has been reported to reduce its surface expression in PDAC cells; inhibiting autophagy in mouse models restores MHC‑I levels and promotes T‑cell responses [195]. Furthermore, lysosomes regulate the degradation, membrane trafficking, and presentation of immune checkpoints including cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), PD‑L1, and CD47 [196, 197]. CMTM6 co‑localizes with PD‑L1 on the plasma membrane and recycling endosomes, inhibiting PD‑L1 lysosomal degradation and thereby sustaining PD‑L1/PD‑1 interaction that dampens T‑cell‑mediated immunity [198].
Functional collaboration and antagonism of lysosomes among cells in the tumor microenvironment
Tumor-associated macrophages: lysosome-driven pro-tumor polarization
As a critical immune cell subset within the TME, the functional reprogramming of tumor-associated macrophages (TAMs) is closely linked to the multifaceted regulatory roles of lysosomes, constituting a key determinant of tumor progression (Fig. 4B) [199, 200]. Lysosomes are deeply involved in tumor invasion, chemoresistance, and immunosuppression by modulating TAM polarization, mediating protease secretion, and regulating ion homeostasis and pH balance. Regarding the regulation of TAM polarization, TAMs predominantly exhibit an M2-like phenotype. Lysosomes promote the shift towards an M2-like state via macroautophagy and CMA [201]. In RCC, M2-like TAMs secrete ferritin to increase iron stores in the TME, aiding tumor cells in evading ferroptosis [202]. In colorectal cancer models, CTSS-mediated autophagic flux facilitates M2 polarization by degrading nuclear factor-kappa B (NF-κB) p65, thereby accelerating tumor growth and liver metastasis [57]. Conversely, Toll-like receptors on the lysosomal membrane can, upon activation, induce M1 polarization via downstream signaling, enhancing anti-tumor immunity [203]. In promoting tumor invasion, tumor cells and TAMs exhibit a significant synergistic effect. Studies indicate that both possess the capacity to secrete cathepsins, co-driving the degradation of the ECM and subsequently promoting tumor cell invasion and metastasis [204, 205]. During chemotherapy-triggered apoptosis, the release of cathepsins from lysosomes into the cytosol and their subsequent perturbation are critical for eliciting tumor cell death. Knockout or inhibition of TAM-derived cathepsins may mitigate chemoresistance [206]. Furthermore, lysosomal ion homeostasis and pH dynamics also regulate TAM function. Weakly basic drugs like chloroquine can elevate lysosomal pH, leading to Ca2 + release via the TRPML1 channel. This activates p38 and NF-κB signaling pathways, inducing the reprogramming of M2-like TAMs towards an M1-like phenotype [207]. Conversely, lactate in the TME can downregulate the lysosomal membrane protein ATP6V0d2 via the mTORC1/TFEB pathway, stabilizing hypoxia-inducible factor 2α (HIF-2α) and promoting M2-like polarization of TAMs and tumor progression [208]. In summary, lysosomes in TAMs regulate macrophage phenotype and function through multi-dimensional mechanisms, offering crucial targets for cancer immunotherapy.
T cells: lysosomal balance in immune activation and exhaustion
Within the TME, CD8+ T cells represent the primary effector cells in antitumor immunity. They induce target cell apoptosis primarily by forming an immune synapse and releasing perforin and granzyme B via lysosomal secretion. Studies have shown that conditional knockout of key autophagy genes (Atg5, Atg14, or Atg16L1) in CD8+ T cells of tumorbearing mice significantly suppresses the growth of various transplanted tumors, including breast and colorectal cancer (Fig. 4C). Concurrently, the proportion of CD8+ T cells differentiating into an effector memory phenotype is increased, accompanied by elevated secretion of cytokines such as interferon-γ and tumor necrosis factor-α. These cytokines not only directly inhibit cancer cell proliferation but also recruit additional immune cells, thereby delaying tumor progression [209]. It should be noted that the aforementioned genes primarily participate in the LC3 lipidation step within the autophagy pathway, a step that can occur without activation of the canonical autophagy initiation machinery – for instance, through the conjugation of ATG8 to single membranes process [210]. Consequently, whether the phenotypic changes observed in CD8+ T cells upon deletion of these genes fully recapitulate the loss of complete autophagic flux warrants further investigation. Additionally, elevated extracellular potassium resulting from necrotic cell death can reduce nutrient uptake by T lymphocytes, thus promoting autophagy. Although heightened autophagy triggers metabolic and epigenetic remodeling that suppresses T cell effector functions, it preserves capabilities such as self-renewal, expansion, and multipotency, preventing T cell exhaustion and overall suppressing tumor progression [211]. Regulatory T cells (Tregs) represent a subset of immunosuppressive T lymphocytes within the TME. Genetic ablation of Atg5 or Atg7 in Tregs impairs their viability and functional stability, thereby inhibiting the growth of colon adenocarcinoma. This phenotypic outcome is ascribed to enhanced activation of mTORC1, elevated c-Myc expression, and augmented glycolytic metabolism arising from impaired autophagy [212]. This suggests that the regulation of T cell autophagy is a key target for tumor immunotherapy. However, its anti-tumor efficacy is highly dependent on the timing of intervention, its intensity, and the cellular heterogeneity within the TME. Key questions regarding the balance threshold between oncogenic and anti-neoplastic effects of autophagy in T cells, along with optimal regulatory strategies and feasible clinical translation, remain unanswered and require further systematic research.
Cancer-associated fibroblasts: lysosome-mediated stromal support
In tumors, another common stromal cell subtype is cancer-associated fibroblasts (CAFs). Mechanistically, CAFs construct and remodel the ECM structure, enabling tumor cell invasion into the TME (Fig. 4D). They also interact with cancer cells or other stromal cells by secreting growth factors, cytokines, and chemokines [213, 214]. CAFs highly express lysosome-associated proteases such as MMPs, which degrade the ECM and release sequestered vascular endothelial growth factor A (VEGF-A), promoting tumor angiogenesis [215, 216]. Simultaneously, MMP-mediated ECM remodeling creates channels for tumor cell invasion. CAFs can drive collective invasion through heterophilic adhesion between N-cadherin on CAFs and E-cadherin on tumor cells [217]. CAFs can also release factors such as IL-6 and chemokine ligand 2 (CCL2) via the lysosome-associated secretory pathway, recruiting immunosuppressive cells, inducing stemness maintenance in cancer stem cells, and enhancing chemoresistance [218–220]. Lysosomal dysfunction may participate in CAF phenotypic switching. Tumor cell-derived exosomes can activate fibroblasts by delivering molecules like miRNAs, inducing alterations in their lysosome-associated secretory profiles [221, 222]. Furthermore, histone acetyltransferase-mediated epigenetic reprogramming is capable of controlling the persistent transcription of lysosome-related genes within CAFs, ultimately shaping a pro-tumorigenic microenvironment [223].
In summary, lysosomes undergo profound functional reprogramming within the tumor microenvironment. Tumor cells drive malignant progression through aberrant expression of lysosome-associated proteins, while stromal and immune cells in the microenvironment, such as TAMs, T cells, and CAFs, modulate pro-tumor polarization, immune homeostasis, and stromal support via differential lysosomal regulation, thereby forming a complex interactive network. This network not only profoundly influences tumor development and therapeutic response but also offers multidimensional intervention targets and a crucial theoretical foundation for LDCD-targeted cancer therapy.
Regulation and effects of LDCD in cancer
LDCD constitutes a dynamic and complex interaction network in tumorigenesis, with increased LMP as its central trigger. Tumor cells undergo lysosomal remodeling that confers inherent susceptibility to LDCD while simultaneously evolving diverse escape mechanisms to evade death. Conversely, activation of LDCD inversely regulates the malignant phenotype of tumor cells. This bidirectional interaction provides critical targets for cancer therapy.
Interaction between LDCD and tumor cells
The sensitivity of tumor cells to LDCD stems from their aberrant lysosomal remodeling characteristics (Fig. 5A). Compared to normal cells, tumor cells commonly exhibit structural alterations such as increased lysosome numbers and swollen volume to adapt to hypoxic and nutrient-deficient microenvironments. Concurrently, abnormal expression of LAMPs and lipids leads to decreased membrane stability [6, 7]. Studies indicate that various lysosome-targeting agents, including cationic amphiphilic drugs (CADs) and cathepsin inhibitors, can selectively induce cancer cell death while exerting minimal effects on normal cells [224]. Among solid tumors including lung cancer, the function of lysosomal CTSB/D/L is elevated in cancer tissues compared to normal tissues (Table 1). Upon LMP, a large amount of cathepsins are released into the cytosol, which can activate the mitochondrial apoptotic pathway by cleaving Bid protein, or drive lipid peroxidation through iron release to induce ferroptosis, and also activate the NLRP3 inflammasome to trigger pyroptosis [14, 35, 154, 160]. In KRAS-mutant pancreatic cancer, decreased V-ATPase activity leads to lysosomal alkalinization, conferring resistance to ferroptosis. Treatment with the V-ATPase activator EN6 effectively inhibits pancreatic cancer progression [71]. In acute myeloid leukemia (AML), the metal chelator Dp44mT accumulates in lysosomes, directly inducing LDCD on one hand, and on the other hand releasing CTSD into the cytoplasm to initiate the mitochondria-dependent apoptotic pathway [225].
Fig. 5.
LDCD in tumors: sensitivity, escape mechanisms, bidirectional regulation, and cancer type-specific pathways. (A)tumor cells exhibit lysosomal abnormalities and elevated cathepsin activity, making them sensitive to LMP-induced cell death. (B)escape mechanisms include membrane repair (ESCRT-III, HSP70↑), lysophagy, and TFEB-mediated lysosomal biogenesis. (C)LDCD activation clears iron-rich cancer stem cells but exerts dual immune effects (CD8+ T cell activation vs. Treg recruitment). (D)cancer types show distinct LDCD pathways: apoptosis (gastric, colorectal), ferroptosis (breast, KRAS-mutant pancreatic), necrosis (melanoma), and others as indicated
Facing the death pressure imposed by LDCD, tumor cells have developed multiple strategies to cope with lysosomal stress, collectively termed the lysosomal damage response mechanism (Fig. 5B). Lysophagy involves numerous proteins and is both labor-intensive and energy-consuming; therefore, cancer cells initially prefer to repair lysosomal damage to prevent leakage of lysosomal contents into the cytoplasm via LMP [2]. Research has found that ESCRT-III can reduce lysosomal content leakage by excising damaged membrane fragments, thereby inhibiting necroptosis in tumor cells [226]. Alternatively, it can upregulate the membrane-protective factor Hsp70 to stabilize the interaction between ASM and the lysosomal lipid BMP, thereby preserving partial enzymatic activity [27, 227]. Severely damaged lysosomes undergo ubiquitination and are subsequently engulfed by autophagosomes, ultimately degraded after fusion with intact lysosomes—a specialized form of autophagy known as lysophagy [228]. In terms of metabolic compensation, drug-resistant tumor cells enhance autophagic flux. Through efficient fusion of autophagosomes and lysosomes, they clear damaged organelles and toxic proteins, reducing the likelihood of LDCD activation [183].
The interaction between LDCD and tumor cells is also reflected in its reverse regulation of malignant phenotypes (Fig. 5C). Effective activation of LDCD can not only directly kill tumor cells but also eliminate cancer stem cells (CSCs) to block tumor recurrence. This is attributed to the significantly higher lysosomal iron storage in CSCs compared to differentiated tumor cells, making this subpopulation specifically susceptible to LDCD-mediated ferroptosis [229]. Furthermore, during LDCD-induced tumor cell death, DAMPs and inflammatory factors are released, enhancing tumor immunogenicity, recruiting CD8+ T cell infiltration, and creating a dual effect of synchronized activation of immune function alongside cell death [172]. However, in immunosuppressive microenvironments, LDCD-induced pyroptosis may release excessive IL-1β, recruiting immunosuppressive cells instead and promoting tumor progression. This dual effect further highlights the complexity of LDCD-tumor cell interactions [230, 231].
In summary, the interaction between LDCD and tumor cells is a dynamic equilibrium process of “sensitivity–evasion–phenotypic regulation”, with lysosomal remodeling in tumor cells serving as the core molecular basis of this interplay. In-depth analysis of LDCD-tumor cell interaction characteristics across different cancer types, along with the targeted design of LMP inducers to overcome evasion mechanisms while regulating LDCD-mediated immune effects, holds promise for constructing efficient LDCD-targeted therapeutic systems, offering new breakthrough directions for cancer treatment.
LDCD-mediated tumor cell death
The death pathways activated following LMP exhibit fundamental heterogeneity across cancer types, driven by tumor-specific metabolic states and molecular contexts (Fig. 5D). In GC, LMP most frequently triggers regulated apoptosis dependent on cathepsins [43, 44]. This mechanism stems from the fact that while GC cells overexpress cathepsins to significantly enhance their invasive and angiogenic capabilities [46, 232], upon LMP, cathepsins leaked into the cytosol can directly cleave and activate the pro-apoptotic protein Bid or inactivate anti-apoptotic proteins like Bcl-2, thereby amplifying apoptotic signals at the mitochondrial level. Concurrently, the leaked enzymes can degrade autophagy-related proteins, disrupting the protective autophagic flux crucial for cancer cell survival. This dual assault of “apoptosis-autophagy flux disruption” is particularly lethal to GC cells that inherently rely on autophagy for survival [33, 233, 234]. In HCC, direct intervention in lysosomal function is also effective in inducing cell death. For instance, delphinidin disrupts cellular homeostasis by inhibiting autophagosome-lysosome fusion, while sphingosine mediates LMP via the TNFα signaling pathway to initiate programmed cell death [22, 235]. Organelle crosstalk mechanisms are more profound, such as microcystin-LR inducing secondary lysosomal dysfunction and apoptosis through the mitochondrial ROS/p53 pathway, or sanguinarine leading to cell death via ROS-dependent mitophagy [236, 237].
In contrast, in breast cancer (particularly triple-negative breast cancer) and KRAS-mutant pancreatic cancer, active lipid metabolic reprogramming and unique susceptibility to ferroptosis render post-LMP cell death more prone to activating ferroptosis, an iron-dependent form of regulated necrosis [238]. LMP can lead to the release of iron ions stored within lysosomes and potentially degrade iron-storage proteins, causing a sharp increase in the cytosolic labile iron pool. This, in turn, catalyzes the generation of massive lipid peroxides via the Fenton reaction. Simultaneously, LMP can indirectly inhibit the cystine/glutamate antiporter or deplete glutathione, weakening the activity of GPX4, the cell’s primary antioxidant defense system. This sabotage of the “braking system” against lipid peroxidation makes metabolically active tumor cells particularly sensitive to ferroptosis [71]. Colorectal cancer presents a more complex scenario, where cells are highly dependent on the autophagy-lysosome pathway, and multiple death pathways exist, ranging from the “lysosomal-mitochondrial apoptosis axis” to MLKL-mediated LMP-associated necroptosis [239, 240]. For example, CTSB released after LMP can specifically cleave Bid protein, inducing mitochondrial pathway apoptosis [241]. Studies also indicate that phosphorylated MLKL translocates to the lysosomal membrane to induce LMP, with released proteases causing organelle damage and ultimately triggering necroptosis [142].
Melanoma and hematological malignancies reveal specific death mechanisms based on lysosomal ion homeostasis and organelle interactions. In metastatic melanoma, compensatory upregulation of the lysosomal Ca2+/Zn2+ channel TRPML1 makes cells sensitive to specific agonists, which can induce rapid Zn2+ -dependent necrosis [40]; acute zinc elevation can also induce mitochondrial-lysosomal functional alterations leading to autophagic cell death [242]. Furthermore, the enzyme 3-hydroxybutyrate dehydrogenase 2 serves a central function in regulating iron transport at mitochondria-lysosome contact sites. Its deficiency leads to lysosomal iron accumulation, rendering mesenchymal-like cells highly sensitive to ferroptosis [243]. In hematological tumors, altered lysosomal membrane properties (e.g., aberrant sphingolipid metabolism, changes in TRPML1 expression) increase their fragility [119, 120], while lysosomes act as key hubs for drug resistance by sequestering targeted drugs or enhancing protective autophagy [244, 245].
This pathway selectivity is not an isolated phenomenon but is directly coupled to core malignant phenotypes of cancer: drug resistance and metastasis. In liver cancer, lysosomes, induced by chemotherapy drugs like cisplatin, can undergo adaptive biogenesis and enhanced autophagy, thereby playing a “protective” role leading to chemoresistance. Conversely, using combination therapy (e.g., PI3K/mTOR inhibitors) to induce LMP can reverse their role to “death promoters,” thereby sensitizing cells to chemotherapy [246]. Similarly, in melanoma, G protein subunit alpha Q mutant cells suppress autophagy via MAPK signaling activation, and combining MEK inhibitors with lysosomotropic agents (e.g., chloroquine) can overcome resistance through synergistic effects [247]. On the other hand, specific lysosomal components directly drive distant metastasis, most typically exemplified by CTSK expression in prostate cancer, which is closely associated with osteoblastic bone metastasis and poor patient prognosis [248, 249]. In melanoma, lysosomal dysfunction can even directly impair anti-tumor immunity—tumor-infiltrating dendritic cells die due to “lysosomal overload”, preventing them from activating CD8+ T cells [250].
Based on these mechanisms, lysosome-targeting therapeutic strategies demonstrate three layers of value: direct cytotoxicity, reversal of drug resistance, and immune modulation. First, directly inducing LMP can selectively kill cancer cells, such as TRPML1 agonists for melanoma, or lysosomotropic alkalinizing agents (e.g., mefloquine) and V-ATPase inhibitors (e.g., Archazolid A) for hematological malignancies [8, 40, 251]. Second, lysosomotropic inhibitors (e.g., hydroxychloroquine, chloroquine) can serve as broad-spectrum “therapeutic sensitizers.” When combined with chemotherapy or targeted therapy (e.g., trametinib, Venetoclax), they synergize by disrupting cellular self-protection mechanisms [120, 247, 252, 253]. For example, in chronic lymphocytic leukemia, combining Venetoclax with lysosome-disrupting agents enhances apoptosis [120, 253]; in chronic myeloid leukemia, combining autophagy inhibitors with poly(ADP-ribose) polymerase (PARP) or tyrosine kinase inhibitors can overcome resistance [254, 255]. Third, modulating the immune microenvironment: the LMP process itself can release DAMPs, activating anti-tumor immunity [256]; preventing lysosomal overload death in immune cells represents a novel strategy to overcome immunotherapy resistance [250].
In conclusion, the LDCD pathway is differentially integrated into the tumor survival and death networks across various cancer types. Future efforts should aim to construct a tumor LDCD sensitivity atlas through multiomics integration, screen key molecular determinants, and develop patient stratification tools, thereby maximizing therapeutic efficacy via precise combination strategies. Taking the lysosomal-associated transmembrane protein 4b (LAPTM4B-35) as an example, early proteomic studies have confirmed its aberrant high expression in multiple cancers, which is closely associated with poor prognosis [63]. A commercially available ELISA kit based on this finding enables noninvasive quantitative detection of serum LAPTM4B-35 and has been applied in a singlecenter retrospective study involving 98 patients with pancreatic ductal adenocarcinoma [257]. The results demonstrated that serum LAPTM4B-35 levels, as an independent prognostic biomarker, effectively distinguish patient subgroups with different survival risks. Although this study remains retrospective in nature, it clearly illustrates a feasible pathway from multiomics screening and biomarker translation to clinical stratification validation, providing an important reference for the precise stratification of LDCD-targeted therapy and laying the foundation for subsequent prospective clinical trials and drug development.
Therapeutic strategies targeting LDCD
The development of lysosome-targeting drugs can be divided into three phases: In the early exploratory phase (pre-2000), research primarily focused on the repositioning of established drugs such as chloroquine and hydroxychloroquine, which were found to exert antitumor effects by disrupting the acidic environment of lysosomes. The drug chemistry optimization phase (2000–2015) centered on structural modifications aimed at enhancing drug-like properties by improving lipophilicity and increasing target specificity. Representative agents from this period include hydroxychloroquine derivatives and ROS inducers. The current research focus (2015-present) has shifted towards novel molecular designs, encompassing lysosome-targeting chimeras (LYTACs) and microenvironment-responsive nanomedicines. Several of these agents have progressed into preclinical or early clinical trial stages. The following section summarizes the research on anticancer drugs based on LDCD and lysosome targeting.
Pharmacological induction of LMP as a therapeutic approach
Based on the mechanism by which drugs interact with lysosomes, LMP inducers can be classified into four categories (Table 2). The first category comprises direct lysosomal membrane disruptors, which compromise membrane integrity through physical insertion or solubilization of the lipid bilayer. The second category includes lysosomal luminal environment disruptors, which induce membrane permeabilization indirectly by altering intraluminal pH, ionic composition, or enzymatic activity. The third category consists of lysosomal trafficking disruptors, which act by modulating lysosomal transport or fusion processes. The fourth category encompasses lysosomal signaling disruptors, which indirectly trigger LMP through calcium- or ROS-mediated cellular signaling pathways.
Table 2.
Representative agents targeting LMP
| Drug | Structure | Classification | Target | Outcome | Model | Ref |
|---|---|---|---|---|---|---|
| Siramesine |  |
CADs |
ASM Inhibitor |
SM ↑ ROS ↑ Autophagy ↓ LMP ↑ |
CRC, OV, BC, Prostate Cancer; Cervical Cancer, Bone Cancer (Cell lines) |
[7, 154, 224] |
| Fluoxetine |  |
CADs |
ASM Inhibitor |
SM ↑ LMP ↑ EGFR pathway ↓ Proliferation ↓ |
Glioblastoma (Mouse model) |
[258] |
| Sertraline |  |
CADs |
NPC2 Inhibitor |
TFEB nuclear translocation ↑ Autophagosome↑ Cholesterol ↑ LMP ↑ Induces ICD Sensitizes immunotherapy |
Osteosarcoma,HCC (Cell lines) Fibrosarcoma (Mouse model) |
[31] |
| Terfenadine |  |
CADs |
ASM Inhibitor |
SM ↑ LMP ↑ Caspase-4/-2/-9 Autophagy ↑ EMT reversal |
Melanoma, NSCLC, BC (Cell lines) |
[7, 259, 260] |
| CQ |  |
CADs | / |
Lysosome pH ↑ LMP↑ Autophagy↓ Chemosensitization |
NSCLC, BC, CRC, Prostate Cancer (Clinical stage) |
[241, 261–263] |
| HCQ |  |
CADs | / |
Lysosome pH ↑ LMP ↑ Autophagy ↓ Chemosensitization |
Solid Tumor (Clinical stage) |
[241, 261–263] |
| Mefloquine |  |
CADs | / |
Lysosome pH ↑ Autophagy ↓ |
AML (Cell lines) (Mouse model) |
[8] |
| Polyphyllin D |  |
CADs |
ASM Inhibitor |
SM ↑ LMP ↑ Chemosensitization |
HCC (Cell lines) (Mouse model) |
[264] |
| Bafilomycin A1 |  |
Disrupt lysosomal environment |
V-ATPase Inhibitor |
Lysosome pH ↑ LMP ↑ Chemosensitization |
T-All, CRC, PC (Cell lines) |
[265, 266] |
| Prosapogenin A |  |
Disrupt lysosomal environment |
V-ATPase Activator |
pH ↓ LMP ↑ Activate caspase-3/8 GSDME dependent pyroptosis |
Anaplastic thyroid cancer (Cell lines) (Mouse model) |
[267] |
| Deox B 7,4 |  |
Disrupt lysosomal environment |
V-ATPase Activator |
pH ↓ LMP ↑ Microtubule inhibition Chemosensitization |
AML (Cell lines) |
[268] |
| GNS561 |  |
Disrupt lysosomal environment |
PPT1 Inhibitor |
Zn2+ ↑ Autophagy ↓ LMP ↑ |
HCC, Cholangiocarcinoma (Clinical stage) | [269] |
| DC661 |  |
Disrupt lysosomal environment |
PPT1 Inhibitor |
Autophagy ↓ LMP ↑ Induces ICD |
Melanoma, CRC (Mouse model) |
[30, 270] |
| WX8 |  |
Disrupt lysosomal trafficking |
PIKfyve Inhibitor |
Lysosomal enlargement Autophagosome accumulation Autophagosome ↓ |
Osteosarcoma (Cell lines) |
[271] |
| Hispidin |  |
Disrupt lysosomal trafficking | Microtubule |
Microtubule depolymerization LMP ↑ Ca2+ ↑ |
Gastric cancer (Cell lines) |
[272] |
| IMB-6 G |  |
Disrupt autophagy | / |
Autophagosome formation↑ Cathepsin activity ↓ Autophagic degradation ↓ LMP ↑ |
Pancreatic Cancer (Cell lines) |
[273] |
| Aloperine |  |
Disrupt autophagy | / |
Autophagosome accumulation pH ↑ Cell cycle arrest Apoptosis |
Glioblastoma (Cell lines) (Mouse model) |
[274] |
| Hexamethylene amiloride |  |
Disrupt upstream signaling | / |
ROS ↑ lysosomal aggregation Mitochondrial swelling |
BC (Cell lines) |
[275] |
Direct lysosomal membrane permeabilizing agents
CADs are a class of compounds characterized by cationic properties and hydrophobic structures that rapidly accumulate in lysosomes and directly interfere with lysosomal membrane stability. They exhibit selective activity against apoptosis resistant and multidrug resistant (MDR) cancer cells and represent the most extensively studied class of LMP inducers to date [8]. Based on clinical use and chemical properties, CADs can be classified into six major categories.
The first class consists of lysosome-targeted antitumor-specific agents. Represented by the amphiphilic amine siramesine, this group inhibits ASM activity by interfering with its binding to the lysosomal cofactor BMP. This leads to sphingomyelin accumulation in lysosomes, membrane permeabilization, and induction of oxidative stress, effectively reversing multidrug resistance [7, 154, 224].
The second category comprises antidepressant drugs, represented by tricyclic antidepressants such as desipramine and selective serotonin reuptake inhibitors such as fluoxetine. The common mechanism of action of these agents lies in their cationic amphiphilic structure, which enables substantial accumulation in acidic lysosomes. Through electrostatic interactions, they interfere with the binding of ASM to its membrane cofactor BMP, thereby inhibiting ASM activity. These agents demonstrate significant tumor growth inhibitory effects in both in vivo and in vitro models [276, 277]. Notably, antidepressants with distinct structural classes exhibit marked heterogeneity in their antitumor efficacy. Fluoxetine, for instance, not only induces LMP and sphingomyelin accumulation by inhibiting ASM, but also effectively suppresses oncogenic EGFR signaling, thereby blocking tumor cell proliferation and survival. Owing to its favorable blood–brain barrier permeability, fluoxetine specifically accumulates in glioblastoma tissues, where it disrupts sphingomyelin metabolism and induces lysosomal stress, effectively inhibiting tumor initiation and progression in both in vitro and in vivo models [258]. In contrast, a recent study has demonstrated that sertraline exacerbates cholesterol accumulation by inhibiting the lysosomal cholesterol transporters NPC intracellular cholesterol transporter 1 (NPC1) and NPC2, while concomitantly promoting TFEB nuclear translocation to upregulate the transcription of multiple lysosomerelated genes [31]. Notably, sertralineinduced lysosomal membrane permeabilization is not merely a cytotoxic event but also converts cancer cells into an immunogenic phenotype, thereby activating a T-cell-mediated adaptive immune response. In preclinical models, this response was capable of suppressing established tumor lesions. A phase III multicenter clinical trial combining sertraline with temozolomide and radiotherapy has been registered (ChiCTR2600123447). Beyond direct antitumor effects, these agents also hold significant adjuvant value in clinical practice. As cancer patients frequently experience anxiety, depression, and other negative emotional states arising from cancer-related pain and chemotherapy-induced gastrointestinal symptoms, antidepressants can alleviate psychological burden while exerting antitumor activity. This dual role—combining antitumor efficacy with psychological intervention—may improve quality of life and potentially extend overall survival [276, 277].
The third category comprises antihistamines, with terfenadine representing a potent example. By virtue of its cationic amphiphilic structure, terfenadine accumulates in acidic lysosomes and inhibits ASM activity, leading to sphingomyelin accumulation and LMP, and exhibits significant growth inhibitory effects across various in vivo and in vitro tumor models [7]. Notably, terfenadine induces cell death through complex and multifaceted mechanisms. In melanoma cells, terfenadine activates caspase-4, caspase-2, and caspase-9, and promotes apoptosis by inducing autophagy through modulation of Ca2+ homeostasis [259]. In advanced drugresistant NSCLC, terfenadine binds to P-gp to enhance chemosensitivity; when combined with epirubicin, it synergistically inhibits cell migration, invasion, and EMT [260].
The fourth category comprises calcium channel blockers, exemplified by amlodipine [7]. As a long-acting antihypertensive agent widely used in clinical practice, amlodipine offers advantages such as high oral bioavailability, a prolonged half-life, and a favorable safety profile. In transformed cell models, amlodipine significantly induces LMP-dependent cell death in c-src-transformed NIH 3T3 cells while exerting minimal effects on non-transformed counterparts, demonstrating favorable tumor selectivity [7]. Compared with other CADs, research on the antitumor activity of calcium channel blockers remains at an early stage, with a lack of systematic in vivo pharmacodynamic evaluations. The optimal tumor types for which they are suited, appropriate combination strategies, and the relationship between their antitumor effects and classical calcium channel blockade remain to be elucidated. Furthermore, whether their antihypertensive activity influences perfusion within the tumor microenvironment—thereby affecting the distribution and efficacy of chemotherapeutic agents—warrants attention in the context of clinical translation.
The fifth category comprises antimalarial drugs. Chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are important members of the CAD family. As weak bases, they accumulate extensively in acidic lysosomes and neutralize intraluminal pH, thereby inhibiting the activity of lysosomal hydrolases that depend on an acidic environment and suppressing autophagic flux [263]. In models such as CRC, CQ in conjunction with the chemotherapeutic agent SN-38 synergistically triggers ROS production and upregulates p53, leading to loss of lysosomal membrane potential and collapse of mitochondrial membrane potential, ultimately enhancing tumor cell killing through the lysosome–mitochondria apoptotic pathway [241]. Additionally, by neutralizing the pH of acidic organelles (e.g., lysosomes and Golgi apparatus), these agents prevent sequestration of chemotherapeutic drugs within acidic vesicles, thereby increasing the effective drug concentration in the cytosol and reversing multidrug resistance [261]. CQ and HCQ have entered multiple cancer clinical trials (Table 3), although cardiac toxicity and retinopathy limit their clinical application [263]. These broad-spectrum lysosome disruptors tend to accumulate in eyes, kidneys and other normal tissues due to wide distribution and long half-life, causing chronic damage and hindering translation. Future optimization focuses on tumor-specific activation and precision targeted delivery, including responsive prodrugs, selective inhibitors and nanocarriers, combined with combination therapy and dose adjustment. Liposomes and polymeric nanoparticles can accumulate in tumors via the enhanced permeability and retention effect or active targeting to induce LMP efficiently while reducing off-target toxicity, facilitating clinical application of LDCD-targeted drugs. Furthermore, because leukemic cells harbor significantly larger lysosomes than normal cells, lysosometargeting strategies preferentially affect AML cells and AML progenitor cells, providing a theoretical basis for novel therapeutic approaches in AML [8].
Table 3.
Preclinical and clinical combination strategies of LMP inducers across cancer types
| Type of tumor | LMP inducer | Combination therapy |
Synergistic mechanism |
State | Outcome | Ref |
|---|---|---|---|---|---|---|
| CRC | CAG | PD-1 antibody |
Immunotherapy CTSB inhibition |
Preclinical |
Inhibits MHC-I degradation Enhances T cell-mediated immunity |
[278] |
| HCQ | Vorinostat |
HDAC inhibitor Autophagy inhibition |
Phase II |
Slightly lower median survival No difference in overall survival |
[279] | |
| CQ |
aFOLFOX Bevacizumab |
Chemotherapy Targeted therapy Autophagy inhibition |
Phase I/II |
Completed, pending further details | ||
| HCC | Polyphyllin D | Sorafenib |
Targeted therapy Autophagy inhibition |
Preclinical | Enhance efficacy of targeted agents | [264] |
| GNS561 |
Atezolizumab Bevacizumab |
Immunotherapy Targeted therapy LMP induction |
Phase IIb |
Completed, pending further details | [269] | |
| HCQ | bTACE |
Chemotherapy Autophagy inhibition |
Phase I/II |
Terminated | ||
| PDAC | HCQ |
Gemcitabine nab-paclitaxel |
Chemotherapy Autophagy inhibition |
Phase II |
Autophagy inhibition and Immune activation Improve pathological response rate & CA 19–9↓ |
[280] |
| HCQ |
Gemcitabine nab-paclitaxel paricalcitol |
Chemotherapy Autophagy inhibition |
Phase II |
Sensitizes chemotherapy | [281] | |
| PIKfyve inhibitor | MAPK pathway inhibitor |
Targeted therapy LMP induction |
Preclinical | Lipid synthesis synthetic lethality effect | [282] | |
|
Cholangio- carcinoma |
GNS561 | Trametinib |
Targeted therapy LMP induction |
Phase Ib/IIa |
Ongoing, pending further details | |
| BC | HCQ | Palbociclib |
Targeted therapy Autophagy inhibition |
Phase II |
Ongoing, pending further details | |
| HCQ | cT-DXd/SG | Targeted therapy Autophagy inhibition |
Phase I/II |
Ongoing, pending further details | ||
| NSCLC | CPTNP | Cisplatin |
Chemotherapy LMP induction |
Preclinical | Sensitizes chemotherapy | [283] |
| HCQ | Erlotinib |
Targeted therapy Autophagy inhibition |
Phase I |
Terminated | ||
| HCQ |
Gemcitabine Carboplatin |
Chemotherapy Autophagy inhibition |
Phase II |
Terminated | ||
| CQ | Gefitinib |
Targeted therapy Autophagy inhibition |
Phase II |
Status unknown | ||
| CQ |
Carboplatin Paclitaxel Bevacizumab |
Targeted therapy Chemotherapy Autophagy inhibition |
Phase II |
Sensitizes chemotherapy Improves clinical efficacy |
[284] | |
| Melanoma | LTANP | PD-1 antibody |
Immunotherapy LMP induction |
Preclinical |
Activates immunity Enhances T cell-mediated immune effects |
[285] |
| GBM | HCQ |
Temozolomide Radiotherapy |
Chemotherapy Autophagy inhibition |
Phase I/II |
Highly toxic Improvement not statistically significant |
[286] |
| CQ |
Temozolomide Radiotherapy |
Chemotherapy Radiotherapy Autophagy inhibition |
Phase I |
Determined safety, pharmacokinetics, and maximum tolerated dose of 200 mg/day in combination with temozolomide | [287] | |
| cystamine dihydrochloride | Radiotherapy |
Radiotherapy Autophagy inhibition |
Preclinica | Sensitizes radiotherapy and may serve as a potential new target for GBM | [288] | |
| Sertraline |
Temozolomide Radiotherapy |
Chemotherapy Radiotherapy Autophagy inhibition |
Phase III ChiCTR2600123447 |
Not initiated | ||
| PC | CQ | Docetaxel |
Chemotherapy Autophagy inhibition |
Phase II |
Terminated early, did not meet study endpoints | |
| CQ |
Abbiterone ABT-263 |
Targeted therapy Autophagy inhibition |
Phase II |
Terminated early, did not meet study endpoints | ||
| Nasopharyngeal carcinoma | HCQ |
Radiotherapy /Chemotherapy |
Radiotherapy /Chemotherapy Autophagy inhibition |
NA |
Ongoing, pending further details | |
| Skeletal metastasis | HCQ | Radiotherapy |
Radiotherapy Autophagy inhibition |
Phase I |
Terminated | |
| Solid tumor | HCQ | MK2206 |
Targeted therapy Autophagy inhibition |
Phase I |
Ongoing, pending further details |
aFOLFOX: Oxaliplatin + Fluorouracil + Leucovorin; bTACE: transcatheter arterial chemoembolization
cT-DXd/SG: Trastuzumab Deruxtecan/Sacituzumab Govitecan
In addition to the synthetic compounds described above, some natural products also possess amphiphilic structures. Polyphyllin D, a steroidal saponin extracted from the traditional Chinese medicine Paris polyphylla, contains a lipophilic aglycone and a hydrophilic sugar chain, enabling its accumulation in lysosomes and marked inhibition of ASM activity [264]. Similarly, the triterpene saponin QS-21, derived from the bark of Quillaja saponaria, exhibits amphiphilic properties and accumulates in lysosomal membranes, thereby influencing lysosomal stability [289]. Macrolide antibiotics, particularly azithromycin, represent another class of natural CADs. When combined with DNA-damaging agents, lysosomal accumulation of azithromycin effectively blocks autophagic flux, leading to substantial accumulation of lysosomes and autolysosomes and further inducing LMP, ultimately promoting apoptosis in NSCLC [290]. Notably, DNA-damaging agents alone typically induce a compensatory resistance mechanism by activating TFEB-mediated lysosomal biogenesis; however, co-administration of azithromycin reverses this compensatory response by blocking autophagic flux, thereby achieving synergistic antitumor effects [290].
Induction of LMP by CADs is often accompanied by secondary effects, including ROS generation and blockade of autophagic flux. Although these events further amplify cellular damage, they fundamentally represent secondary responses following lysosomal dysfunction. The cancer-selective activity of CADs arises from the decreased stability of lysosomes in tumor cells; nevertheless, tumor cells may activate intrinsic compensatory mechanisms to partially repair LMP induced by these agents, attenuating monotherapy efficacy. Consequently, in most clinical settings, CADs are frequently combined with chemotherapeutic agents to achieve chemoradiosensitization and enhance therapeutic efficacy [154, 253].
Lysosomal luminal environment disruptors
V-ATPase serves as the core proton pump responsible for maintaining the acidic pH of lysosomes; its dysregulation directly leads to lysosomal dysfunction. V-ATPase inhibitors block proton transport, resulting in lysosomal alkalinization. Representative agents include bafilomycin A1, archazolid, manzamine A, ZT-25, diphyllin, and cleistanthin A. Bafilomycin A1, a classical V-ATPase inhibitor, directly inhibits proton translocation and induces LMP in tumors including CRC and pancreatic cancer, promoting cathepsin release and activating apoptotic pathways [265, 266]. In T-cell acute lymphoblastic leukemia (T-ALL) cells, archazolid enhances chemosensitivity by interfering with lysosomal acidification, offering a potential novel therapeutic strategy for T-ALL [291]. Furthermore, archazolid reduces CTSB activity and significantly decreases lung metastasis in breast cancer models through LMP-mediated lysosomal dysfunction [292]. Additional novel inhibitors—including manzamine A, ZT-25, diphyllin, and cleistanthin A—have been shown to induce Sphase arrest, apoptosis, or autophagyassociated cell death in tumor cells by targeting lysosomal V-ATPase [293–296].
Notably, V-ATPase activators also exhibit antitumor potential by enhancing enzyme activity. In anaplastic thyroid cancer (ATC), a highly aggressive malignancy lacking effective treatment options, the bioactive natural product prosapogenin A significantly upregulates the expression of key V-ATPase subunits ATP6V1A, ATP6V1B2, and ATP6V0C, leading to excessive lysosomal acidification, exacerbating LMP. The released cathepsins activate caspase-8/3, which cleave GSDME, ultimately inducing pyroptosis. Prosapogenin A demonstrates potent anti-ATC activity both in vitro and in vivo [267]. In AML, the novel smallmolecule compound deoxysappanone B 7,4′dimethyl ether (Deox B 7,4) potentiates lysosomal acidification by increasing V-ATPase function and, combined with its microtubule-inhibitory properties, induces lysosomal disruption. This mechanism distinguishes Deox B 7,4 from other microtubule inhibitors such as colchicine and vinblastine and reveals a new paradigm by which certain microtubule inhibitors modulate lysosomal function through V-ATPase regulation [268]. Moreover, combining V-ATPase modulators with chemotherapeutic agents such as cisplatin and anthraquinones can reverse the acidic tumor microenvironment and reduce intracellular drug sequestration, significantly enhancing therapeutic efficacy [297, 298]. Collectively, V-ATPase modulators disrupt lysosomal homeostasis by inducing LMP, providing effective therapeutic strategies for multiple tumor types. Combination regimens, in particular, hold promise for overcoming drug resistance, although subty-pespecific targeting and protection of normal tissues warrant further investigation.
As detailed above, one of the primary mechanisms of action of LMP inducers is the inhibition of ASM. In addition, palmitoyl protein thioesterase 1 (PPT1), a key enzyme responsible for depalmitoylation within lysosomes, has emerged as an important target for lysosome-directed antitumor therapy, with representative agents including GNS561 and DC661 [30, 269]. GNS561, a clinical-stage PPT1 inhibitor with strong liver tropism, exhibits marked hepatic targeting and antitumor activity by virtue of its lysosomeaffinity properties. By specifically inhibiting lysosomal PPT1, GNS561 promotes intralysosomal accumulation of free zinc ions, suppresses cathepsin activity, blocks autophagic flux, and disrupts mTOR localization, ultimately leading to LMP, caspase activation, and cell death [269]. This agent demonstrates potent antitumor efficacy in human HCC and two in liver cancer models, and has successfully accomplished a global Phase I/IIa clinical trial for the treatment of liver cancer (NCT03316222). A Phase Ib/IIa trial evaluating GNS561 in combination with trametinib for advanced KRAS-mutant cholangiocarcinoma (NCT05874414) is currently ongoing [299, 300].
Inhibitors of lysosomal trafficking and homeostasis
Inhibitors of lysosomal trafficking and fusion can indirectly induce LMP by interfering with lysosomal membrane dynamics. PIKfyve inhibitors represent a prominent class of such agents. PIKfyve is a key kinase that catalyzes the conversion of PI(3)P to PI(3,5)P₂ and plays a central role in the dynamic regulation of endolysosomal membranes. WX8, a PIKfyve inhibitor, disrupts lysosomal tubule fission, transport of molecules to lysosomes, and heterotypic autophagosome–lysosome fusion by specifically binding to PIKfyve, without affecting lysosomal acidity or homotypic fusion [271]. A potent member of this class, WX8 exhibits greater cytotoxicity against A375 melanoma cells than hydroxychloroquine or chloroquine, and exerts its effects selectively in autophagy-dependent tumor cells [271]. Additionally, certain natural productderived compounds, such as hispidin, have been shown to trigger LMP through microtubule depolymerization. Hispidin induces microtubule depolymerization, leading to aberrant lysosomal trafficking and subcellular localization, which in turn compromises lysosomal membrane stability [272].
Autophagy pathway inhibitors targeting lysosomes
Blockade of autophagic flux is a common downstream consequence of many LMP inducers, stemming from impaired lysosomal function. When lysosomal membrane stability is compromised or intraluminal pH is perturbed, autophagosome-lysosome fusion is disrupted, blocking the degradation of formed autophagosomes and resulting in autophagic arrest at the late stage. Notably, both favorable and adverse correlations linking autophagy to cell death have been documented in diverse cancer cell types [301–303]. Therefore, the application of autophagy inhibitors or activators demands prudent evaluation and should be tailored to the specific context. IMB-6G, an N-substituted matrine derivative, acts as a novel autophagy inhibitor and exhibits potent cytotoxicity against pancreatic cancer cells. Its mechanism involves early promotion of autophagosome accumulation, accompanied by blockade of autophagic degradation through attenuation of lysosomal cathepsin activity, ultimately triggering LMP and release of CTSB and CTSD [273]. Aloperine, a latestage autophagy inhibitor, impairs autophagosome–lysosome fusion and induces ROS production. In glioma models, its combination with temozolomide reduces toxicity and enhances therapeutic efficacy [274]. Furthermore, the CAD compound QS-21 has been shown to synergize with the type I ribosome-inactivating protein MAP30 at low concentrations. This combination suppresses lysosomal autophagy, preventing timely clearance of damaged lysosomes and resulting in extensive leakage of lysosomal contents (e.g., cathepsins) into the cytosol, ultimately triggering LDCD [289].
Targeting upstream signaling pathways to trigger LMP
Certain drugs act on lysosomes indirectly rather than directly, triggering LMP by activating specific cellular signaling pathways. Based on the initiating signal, these agents can be further classified into calcium signaling modulators and oxidative stress inducers.
As discussed earlier, calpains mediate increased lysosomal membrane permeability by cleaving Hsp70 and LAMP2 [18, 143]. ATP, an endogenous bioactive molecule, induces calcium influx by activating the purinoceptor 7 receptor on immune cells, thereby regulating TRPM2 and two-pore channels on late endosomal and lysosomal membranes, ultimately leading to LMP and cathepsin release [304]. In GC cell lines, hispidin-induced LMP and subsequent cell death were not reversed by the pancaspase inhibitor z-VAD; however, cell viability was significantly restored upon treatment with the calcium chelator BAPTA, confirming that lysosomal calcium release plays a central regulatory role in hispidin-induced LMP and cell death [272]. These findings suggest that calcium released from lysosomes following LMP may constitute a critical factor in triggering cell death.
ROS inducers promote ROS generation, which oxidatively modifies lysosomal membrane lipids and proteins, leading to decreased membrane stability [305]. Certain DNA-damaging agents, such as bleomycin, generate ROS during their activation process, thereby inducing LMP and inhibiting autophagic flux and lysosomal degradation [17]. Hexamethylene amiloride (HMA), a C5 derivative of amiloride, exhibits broad-spectrum cytotoxicity against breast cancer cells while displaying low toxicity toward normal mammary epithelial cells. This selective toxicity arises from the heightened sensitivity of breast cancer cells to HMA-induced cell death. HMA induces perinuclear clustering of lysosomes, accompanied by enhanced autophagic degradation and ROS accumulation, ultimately triggering a non-caspase-dependent, autophagy-independent programmed necrosis that exerts antitumor effects. This effect is significantly attenuated by ROS scavengers or cathepsin inhibitors, further confirming the synergistic role of ROS and lysosomal dysfunction in HMA-mediated cancer cell clearance [275]. Other agents, such as arsenic trioxide, modulate ROS metabolism by inhibiting catalase activity, thereby indirectly regulating LMP-associated cell death pathways [306]. Naringin downregulates the PI3K/AKT/mTOR signaling pathway and induces ROS generation, activating the ERK1/2-p38 MAPK signaling cascade, which in turn upregulates the lysosomal membrane protein LAMP1, ultimately triggering LDCD in human gastric adenocarcinoma cell lines [307]. Octyl syringate induces lysosomal destabilization and suppresses autophagic flux, displaying preferential cytotoxicity against various cancer cells [308]. Collectively, targeting ROS-mediated LMP holds considerable promise for the treatment of malignancies, and further development of related agents may offer new directions for clinical therapy.
Novel lysosome-targeting agents
As a central intracellular degradation hub, the lysosome facilitates protein clearance via two primary pathways: the autophagy-lysosome pathway, which degrades cytoplasmic proteins and damaged organelles, and the endocytosis-lysosome pathway, which processes extracellular proteins. Leveraging this functional duality, emerging technologies such as antibody-drug conjugates (ADCs) and LYTACs exploit lysosomal trafficking to release therapeutic payloads. These approaches transcend the limitations of traditional pharmacology by enabling targeted degradation of previously “undruggable” proteins, offering novel therapeutic avenues for cancer, neurodegenerative disorders, and other diseases. Consequently, they have become a major research focus within the field of targeted protein degradation.
Antibody-drug conjugates
ADCs represent a rapidly advancing class of targeted cancer therapeutics, ingeniously combining the precise targeting specificity of monoclonal antibodies with the robust cytotoxic potency of small-molecule payloads. The core design involves covalently linking a monoclonal antibody to a cytotoxic effector molecule via a chemical linker, enabling targeted delivery and release of the cytotoxic agent to cancer cells (Fig. 6A). A pivotal element of this targeted release mechanism relies on lysosomal proteases (such as CTSB), which are frequently overexpressed in human cancers and can specifically recognize and cleave various peptide-based linker sequences. When ADCs bind to antigens expressed on the cancer cell surface through their antibody moiety, they are internalized into the tumor cell. The valine-citrulline (Val-Cit) linker they carry is then recognized and efficiently cleaved by intracellular lysosomal proteases, precisely releasing the cytotoxic payload. This mechanism aims to kill cancer cells while minimizing damage to normal cells [309, 310]. However, clinical application revealed that the Val-Cit sequence is susceptible to nonspecific cleavage by various proteases, leading to off-target toxicities such as neutropenia and thrombocytopenia. This may be attributed to premature cleavage of the Val-Cit PABC linker by neutrophil proteases [311, 312]. Consequently, alternative linker designs were developed, such as the cathepsin-cleavable GGFG tetrapeptidyl-aminomethoxy linker, now employed in ADCs like DS-8201a (Enhertu) and SHR-A1811 [313]. Recent results from the DESTINY-Breast09 clinical trial (NCT04784715) demonstrated that Enhertu combined with pertuzumab for first-line treatment achieved a median progression-free survival (PFS) of 40.7 months, outperforming the 26.9 months observed with the standard paclitaxel plus trastuzumab and pertuzumab regimen. Based on this, Enhertu has been granted approval by FDA for the first-line treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, in combination with pertuzumab. [314].
Fig. 6.
Schematic representation of targeted therapeutic strategies leveraging lysosomal degradation. (A) ADCs are composed of a monoclonal antibody, a cleavable linker, as well as a cytotoxic payload. Upon internalization, ADCs undergo lysosomal degradation, releasing the payload to induce DNA damage or microtubule disruption and ultimately cause cell death. (B) Lysosome-targeted protein degradation strategies include ATTEC, AUTAC, LYTAC, and AUTOTAC, which direct target proteins for lysosomal degradation. (C) Chemical structures of representative AUTAC molecules. First-generation AUTACs (AUTAC1 and AUTAC2) contain MetAP2 and FKBP12 binders as warheads, respectively. Second-generation AUTAC 10f is structurally optimized by removing the cysteine substructure from the linker. (D) Schematic of lysosome-targeting nanoparticle strategies. Left: exogenously stimulated nanoparticles directly disrupt lysosomal membranes. Right: drug-loaded, pH-responsive nanoparticles (e.g., vC@cLAVs) trigger drug release to induce tumor cell death and immune activation
Furthermore, a recent study utilized the HyCoSuL platform to design linkers incorporating unnatural amino acids. These linkers also achieved precise responsiveness to CTSB or CTSL, demonstrating high selectivity and excellent plasma stability in HER2-positive breast cancer models [315]. As of January 2026, 11 ADCs containing cathepsin-cleavable linkers have received regulatory approval (Table 4). Examples include Brentuximab vedotin for Hodgkin lymphoma and Disitamab Vedotin for HER2 positive urothelial carcinoma and GC. Following internalization via endocytosis, these ADCs undergo cathepsin-mediated cleavage to release cytotoxic payloads such as MMAE, enabling precise tumor cell killing.
Table 4.
Approved ADCs with cysteine cathepsin-cleavable linkers
| ADC | Linker | Payload | Target | Cancer |
|---|---|---|---|---|
| Brentuximab vedotin (Adcetris®) | mc-ValCitPABC | MMAE | CD30 |
Hodgkin Lymphoma Systemic anaplastic large cell lymphomas |
| Polatuzumab vedotin (Polivy®) | mc-ValCitPABC | MMAE | CD79b | Diffuse Large B-Cell Lymphoma |
| Trastuzumab deruxtecan (Enhertu®) | mc-GGFG-aminomethoxy | Deruxtecan, Dxd | HER2 |
HER2+ BC; NSCLC; GC Gastro oesophageal junction |
| Enfortumab vedotin (Padcev®) | mc-ValCitPABC | MMAE | Nectin4 | metastatic urothelial Carcinoma |
| Disitamab Vedotin (Aidixi®) (NMPA) | mc-ValCitPABC | MMAE | HER2 | urothelial Carcinoma; GC |
| Trastuzumab-rezetecan SHR-A1811 (NMPA) | mc-GGFG-aminomethoxy | SHR169265 | HER2 | NSCLC |
| Loncastuximab tesirine (Zynlonta®) | mc-ValCitPABC |
SG3199 PDB dimer |
CD19 | Diffuse Large B-Cell Lymphoma |
| Tisotumab vedotin (Tivdak®) | mc-ValCitPABC | MMAE | Tissue factor | Cervical Cancer |
| Moxetumomab pasudotox (Lumoxiti®) | mc-ValCitPABC | PE38 | CD22 | Hairy cell leukemia |
| Telisotuzumab Vedotin | mc-ValCitPABC | MMAE | c-Met | NSCLC (non-LUSC) |
| Datopotamab Deruxtecan (Datroway®) | mc-GGFG-aminomethoxy | Deruxtecan, Dxd | Trop2 | HR+ HER2- BC |
Lysosome-targeting Degraders
While PROTACs have seen rapid development, their scope is primarily limited to intracellular proteins, leaving extracellular and secreted proteins largely inaccessible. These extracellular proteins are often critically involved in cancer, aging, and autoimmune diseases. Lysosome-targeting degraders address this gap by offering excellent targeting capabilities against both intracellular and membrane-bound aberrant or disease-related proteins (Fig. 6B).
In 2019, the team led by Professor Bo Xun Lu at Fudan University developed a novel targeted protein degradation strategy named autophagosome-tethering compounds (ATTECs). They synthesized a series of compounds capable of linking mutant huntingtin protein (mHTT) to LC3 [316]. ATTECs are bifunctional chimeric molecules that tether a protein of interest (POI) to a component of a specific protein degradation machinery (PDM), such as the autophagosome membrane protein LC3. Operating independently of ubiquitination and with a lower molecular weight, ATTECs can degrade not only proteins but also non-proteinaceous biomacromolecules like lipids, conferring promising drug-like properties. In 2022, a study by Dong and colleagues designed a series of bifunctional compounds linking a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor to an LC3-binding moiety via different linkers. These compounds demonstrated the ability to degrade NAMPT in OV cell lines [317]. NAMPT is the rate-limiting enzyme converting nicotinamide to nicotinamide mononucleotide. Reported as a potential oncoprotein and therapeutic target, it is implicated in various cancers including colon and prostate cancer. In 2025, the team led by Shi Linqi proposed a nanoparticle-based ATTEC platform utilizing mixed-shell polymeric micelles [318]. This strategy employs pH-responsive regulation, enabling the nano-ATTEC to undergo rapid transformation in the acidic tumor microenvironment, thereby enhancing cellular uptake and concurrently activating the autophagy pathway to achieve efficient degradation of target proteins such as bromodomain-containing protein 4 (BRD4) and AR. This approach provides a novel perspective for designing targeted protein degradation drugs.
Additionally, in 2019, the research team headed by Hirokazu Arimoto exploited the selective degradation machinery of group A streptococcus (GAS) to engineer a chimeric molecule endowed with targeted protein degradation activity, termed autophagy-targeting chimeras (AUTACs), which is also recognized as the first-generation AUTACs [319, 320]. These consist of three parts: a degradation tag, a linker, and a ligand for POI. The first-generation AUTACs selected a cyclic guanosine monophosphate (cGMP) derivative as the autophagy tag to induce endogenous S-guanylation, and all contained a cysteine substructure [320]. For instance, AUTAC2 (Fig. 6C) engineered to induce the degradation of FK506-binding protein 12 (FKBP12), and the non-covalent synthetic ligand “SLF” for FKBP could be degraded by the AUTAC system at a concentration of 10 µM [320]. Similarly, another research team linked the BRD4 inhibitor JQ1 and GW5074 to obtain AUTAC 10f (Fig. 6C), which induced apoptosis and caused G1 phase arrest to exhibit anti-proliferative activity in various tumor cells [321]. Upregulation of BRD4 expression shares a close association with the development and progression of cancers such as lung cancer, BC, AML, and liver cancer. However, the cysteine substructure in these early AUTACs could trigger unintended activation of protein kinase G, while the negative charge of the cyclic phosphate moiety might hinder the permeability of the cell membrane [320, 322]. Based on preliminary studies, Professor Hirokazu Arimoto’s team conducted structure-activity relationship (SAR) studies on AUTACs. They found that replacing the cysteine substructure with a pyrazole ring not only resolved the issues of nonspecific activation and membrane permeability but also significantly enhanced activity, successfully enabling FKBP12 protein degradation and clearance of dysfunctional mitochondria [322]. These findings illustrate the feasibility of AUTACs and suggest their potential for broad application in discovering future autophagy-related therapeutics. However, the specific mechanisms, such as how S-guanylation or its analogs induce ubiquitination or affect autophagic flux, remain insufficiently elucidated.
In 2020, a research team from Stanford University reported a lysosome-targeting technology for degrading extracellular proteins, termed LYTACs [323]. A LYTAC molecule primarily consists of two parts connected by a linker: one end is an antibody, peptide, or a small-molecule ligand capable of recognizing and binding to the target protein, and the other end is an oligosaccharide structure that recognizes and associates with a cell-surface lysosome-targeting receptor (LTR), including the cation-independent mannose-6-phosphate receptor (CI-M6PR). This forms a ternary complex that is internalized via endocytosis. Once inside the cell, the complex is trafficked to and degraded within lysosomes. The target protein is enzymatically degraded, while the dissociated LTR is recycled back to the cell surface to mediate further rounds of target protein internalization. Recently, the research group headed by Professor Yanfeng Gao from the School of Pharmaceutical Sciences, Sun Yat-sen University, proposed a covalent chimeric peptide-targeted degradation platform, designated as Pep-TACs. By incorporating a long and flexible aryl sulfonyl fluoride group, Pep-TACs enable proximity-driven cross-linking after binding to the target protein. Studies found that Pep-TACs can effectively target and degrade membrane proteins, particularly PD-L1, and exhibit the capacity to cross the blood-brain barrier, thereby providing a novel therapeutic strategy for the treatment of brain disorders [324]. A significant advantage of this strategy is the marked reduction in hematologic toxicity. For instance, magrolimab, a widely studied CD47-targeting antibody, can cause severe anemia by binding to CD47 on red blood cells. However, mature erythrocytes lack lysosomes and endosomes. Utilizing a LYTAC approach to degrade CD47 via the lysosomal pathway can effectively circumvent this adverse effect. In melanoma and breast cancer models, PPS/RS17–M6P3 efficiently degraded CD47 both in vitro and in vivo through the lysosomal pathway, while simultaneously promoting macrophage polarization towards the M1 phenotype. This not only activated anti-tumor immunity and inhibited tumor growth but also effectively reduced toxicity to red blood cells [325]. In 2022, the team led by Professor Yong Tae Kwon at Seoul National University in South Korea developed another class of autophagy-targeting chimeras named AUTOphagy-targeting chimeras (AUTOTACs) [326]. AUTOTACs consist of three parts: a ligand for the POI, a ligand targeting the ZZ domain of the autophagy receptor p62, and a linker. Unlike AUTACs, AUTOTACs operate by directly recruiting the POI to the p62 receptor, representing a direct binding mechanism for substrate recognition. Through 3D modeling and structure-activity relationship studies of the p62 ZZ domain, the researchers screened compounds such as YOK-2204. Subsequently, they synthesized various AUTOTACs by connecting the p62-ZZ ligand to POI ligands via PEG linkers. Experiments confirmed that these molecules could mediate the degradation of oncoproteins as well as misfolded protein aggregates, providing a potential therapeutic approach for cancer and neurodegenerative diseases. Notably, the efficacy of AUTOTACs appears less dependent on linker length, offering greater flexibility in their design [326].
In summary, lysosome-targeting degradation technologies such as LYTACs and AUTACs specifically recruit lysosomes to degrade target proteins, thereby overcoming the limitations of conventional small molecule inhibitors and offering a novel strategy for treating tumors driven by undruggable targets, with broad clinical application prospects. Nevertheless, several critical challenges remain for their clinical translation. First, chimeric molecules generally possess a high molecular weight, which markedly reduces cell penetration efficiency and oral bioavailability, thereby limiting their in vivo delivery efficiency and tissue penetration in solid tumors. Second, off-target effects constitute a major risk, as nonspecific binding may disrupt lysosomal homeostasis in normal tissues and lead to systemic toxicity. Third, certain chimeric molecules can activate both innate and adaptive immune responses, generating immunogenicityrelated adverse reactions that compromise therapeutic safety. Fourth, their complex pharmacokinetic profiles—influenced by factors such as lysosomal metabolism, protein binding rates, and clearance pathways—affect effective drug exposure and efficacy stability, posing substantial challenges for clinical dose design and safety evaluation. Future efforts should focus on strategies including molecular structure optimization, targeted delivery system engineering, and immunogenicity modification to advance the clinical translation and application.
Stimuli-responsive Nanomedicines
Conventional cancer therapies are often limited by suboptimal efficacy and significant side effects. Nanoparticles, with their advantages of facile preparation and engineerability, serve as ideal drug carriers. By synergizing with the acidic environment and functional characteristics of lysosomes, they provide innovative directions for cancer treatment. Current nanocarrier strategies designed based on lysosomal properties include directly disrupting tumor cell lysosomes, enabling escape of therapeutic agents from tumor cell lysosomes, and facilitating escape from immune cell lysosomes (Fig. 6D).
Direct lysosomal disruption in tumor cells: exogenous stimuli (magnetic, optical) can enable nanocarriers to generate mechanical force or ROS, directly damaging tumor cell lysosomal membranes, inducing LMP, and subsequently mediating cell death. The team of domenech conjugated iron oxide magnetic nanoparticles (MNPs) with an EGFR ligand, allowing specific recognition of tumor cells overexpressing EGFR [327]. Results demonstrated that under an alternating magnetic field, EGFR-targeted MNPs selectively induced LMP in EGFR-overexpressing tumor cells, ultimately killing them. The nano-photosensitizer BDQ-NP generates ROS upon light irradiation to induce LMP, demonstrating excellent efficacy with no systemic toxicity in colorectal cancer and orthotopic breast cancer models via high-efficiency photodynamic therapy (PDT) [328]. Additionally, some nanomedicines can directly disrupt lysosomes, causing LMP and triggering various cell death modalities. Nadeem and colleagues engineered a virus-spike tumor-activatable pyroptotic agent (VTPA) [329]. VTPA features a virus-like spiked morphology, comprising an organosilica-coated iron oxide nanoparticle core and spike-like manganese dioxide protrusions. After systemic administration, it accumulates in tumors, promoting tumor cell lysosomal rupture while being degraded by overexpressed glutathione in the tumor, releasing manganese ions and iron oxide nanoparticles. These components synergistically activate the NLRP3 inflammasome, inducing pyroptosis. Similarly, NP-NH-D5 undergoes a charge reversal within tumor cell lysosomes, transitioning from nanoparticles to nanofibers, thereby disrupting lysosomes and subsequently triggering GSDMD -mediated pyroptosis [330]. The “nano-rocket” UIOQM-IQ is composed of ultra-small iron oxide(UIO) nanoparticles, a CTSB-cleavable peptide, an aggregation-induced emission fluorophore QMTPA, and the Tolllike receptors 7 and 8 (TLR7/8) agonist imidazoquinoline [331]. Under the acidic tumor microenvironment, it releases imidazoquinoline to enhance antigen-presenting cell activation. CTSB localized in tumor lysosomes specifically cleaves the peptide linker, inducing aggregation of QMTPA and UIO nanoparticles, enabling fluorescence “off-on” switching and T1–T2 magnetic resonance contrast changes, aiding tumor visualization and real-time monitoring. Concurrently, UIO aggregation leads to lysosomal rupture, inducing ICD via a ferroptosis pathway, enhancing tumor immunogenicity and promoting antigen presentation.
Lysosomal Escape Strategies: Another core strategy involves designing pH-responsive or photo-responsive nanocarriers that capitalize on the microenvironmental discrepancies between tumor and normal cells or respond to exogenously controllable stimuli. Upon entering tumor cells, these carriers can undergo structural changes triggered by the acidic lysosomal environment or specific effects generated by light irradiation, breaching the lysosomal membrane barrier to efficiently release payloads (drugs/nucleic acids). Alternatively, they can target immune cells (e.g., T cells, antigen-presenting cells) to facilitate the escape of immunomodulatory molecules from lysosomal degradation, fully activating anti-tumor immune responses and thereby enhancing the precision and efficacy of immunotherapy. Gang-Gang Yang et al. designed a dual-drug-loaded nanoparticle, Fu/LD@RuCD (Fu: 5-fluorouracil; LD: lonidamine; Ru: Ru(phen-ad)₃₂) [332]. On one hand, the RuCD nanocarrier generates ROS under visible light irradiation to induce LMP. On the other hand, the nanoparticle releases chemotherapeutic drugs in the weakly acidic lysosomal environment, leading to mitochondrial dysfunction and cancer cell apoptosis. Similarly, verteporfin-containing liposomes disrupt lysosomal membranes under PDT, promoting oxaliplatin escape from lysosomes and enhancing its accumulation and cytotoxic effects within the nuclei of pancreatic cancer cells [333]. A recent study reported a supramolecular artificial nano-AUTAC (GM NPs) constructed via supramolecular interactions between an AUTAC molecule GN (an indoleamine 2,3-dioxygenase (IDO) degrader) and the nucleoside analog methotrexate [334]. The nanostructure can precisely localize to cancer cells, where the supramolecular interaction is disrupted in the acidic environment, releasing methotrexate for antitumor therapy. Furthermore, overactive cysteine cathepsins in TAM lysosomes can hinder cross-presentation and inhibit CD8+ T cell activation. The team of Chang Cui developed a DNA nanodevice, E64-DNA, which precisely targets lysosomes in murine TAMs, inhibiting their specific cysteine cathepsin activity. This enhances the antigen cross-presentation capability of TAMs, activates CD8+ T cells, and slows tumor growth. Combined with cyclophosphamide, this nanomaterial achieved sustained tumor regression in a triple negative breast carcinoma (TNBC) mouse model [335].
To summarize, as a crucial target in cancer treatment, the unique acidic environment and functional properties of lysosomes provide a vital basis for the precise design of nanomaterials. Various lysosome-targeted nanomedicines (e.g., LTANP, CPTNP, E64-DNA) directly kill tumor cells or activate antigen cross-presentation and CD8+ T cell-mediated anti-tumor immunity by affecting autophagy pathways or inducing aggregation/rupture, effectively overcoming the bottlenecks of conventional therapies. When combined with chemotherapeutic drugs or immune checkpoint inhibitors, some formulations achieve sustained tumor regression, fully demonstrating the core advantage of nanomaterials in targeting lysosomes to activate immunity. This opens a promising new path for precise immunotherapy of cancers, particularly for difficult-to-treat subtypes like triple-negative breast cancer.
Combination therapy strategies
The core value of therapeutic strategies targeting LDCD lies not only in their ability to directly induce cancer cell death but also in their potential to systematically reshape tumor vulnerabilities. This facilitates synergy with existing treatments, overcomes drug resistance, and enhances therapeutic efficacy. Therefore, combination therapy represents a critical pathway for translating LDCD from bench to bedside (Table 3).
Targeting lysosomal function can significantly sensitize tumors to radiotherapy and chemotherapy, providing a key strategy to overcome acquired resistance. The lysosomal/autophagy pathway is a core mechanism underlying cancer cell resistance. In PDAC, for instance, the dense inflammatory stroma within the tumor microenvironment and activated autophagy work together to mediate therapeutic resistance [281]. Hydroxychloroquine, as a well-established lysosomotropic agent, demonstrates significant synergistic value in combination regimens, supported by substantial clinical evidence. A randomized phase II study (NCT01978184) conducted by a team at the University of Pittsburgh showed that adding HCQ to a neoadjuvant chemotherapy regimen of gemcitabine plus nab-paclitaxel in patients with resectable PDAC significantly improved pathological tumor response rates and serum biomarker responses, achieving dual effects of autophagy inhibition and immune activation [280]. Another phase II study (NCT04524702) further confirmed that combining HCQ with the vitamin D receptor agonist paricalcitol significantly enhanced the efficacy of gemcitabine/nab-paclitaxel against PDAC and effectively remodeled the tumor immune microenvironment [281]. However, a phase I/II trial (NCT00486603) in glioblastoma multiforme (GBM) showed that the cohort receiving HCQ combined with temozolomide experienced significant toxicity without statistically meaningful patient improvement [286]. Notably, GBM is a brain malignancy generally resistant to radiotherapy. Recent research found that inhibiting transglutaminase 2 (TGM2) to block aberrant autophagosome-lysosome fusion can effectively overcome this radioresistance, providing a new target for clinical radiosensitization [288]. This highlights the necessity of fully considering tumor heterogeneity when designing lysosome-targeted combination therapies and precisely selecting compatible strategies. Additionally, Christopher and colleagues designed a cell-penetrating transformable peptide nanoparticle (CPTNP) that exhibits toxicity against NSCLC cells in the low-micromolar range and enhances the toxicity of cisplatin in combination [283].
Current cancer therapy has entered an era of precision medicine, where personalized treatment strategies formulated using techniques like immunohistochemistry are mainstream. The combination of natural products with targeted agents shows significant synergistic potential. For example, combining polyphyllin D with sorafenib (a Raf inhibitor) enhances the latter’s anticancer activity in vitro and in vivo [264]. Inhibiting the lysosomal lipid kinase PIKfyve forces pancreatic cancer cells to rely on KRAS-MAPK pathway-driven lipogenesis, creating a synthetic lethal effect with inhibitors of this pathway (e.g., MRTX1133, trametinib), which effectively eliminated tumor burden in a variety of preclinical human and mouse models [282].
Immunotherapy is another crucial direction for combination therapy. LMP and subsequent cell death release DAMPs, activating anti-tumor immunity and converting “cold” tumors to “hot” ones. For instance, LTANPs efficiently accumulate within tumors, selectively target and aggregate in cancer cell lysosomes to induce LMP, and trigger ICD by disrupting the autophagy-lysosome pathway [285]. In melanoma models, LTANPs successfully elicited a robust anti-tumor immune response. Combining them with a PD-L1 antibody further enhanced T cell-mediated immunity, significantly inhibiting tumor recurrence and metastasis. The PD-L1 degrader B3, developed based on protein degradation technology, can reduce PD-L1 expression levels by inducing its endolysosomal degradation, effectively inhibiting tumor growth in vivo [336].
Furthermore, lysosomal cathepsins have become a research hotspot for combination therapies. CTSB inhibitors CA-030 and CA-074, which specifically bind to the catalytic cysteine residue, effectively reduced tumor burden and lung metastasis in a metastatic melanoma mouse model. CA-074 also inhibited breast cancer bone metastasis progression [337, 338]. These findings suggest that protease inhibitors targeting different metastatic pathways in breast cancer could synergize with standard chemotherapy (e.g., paclitaxel), offering new strategies to overcome resistance [206]. The reversible inhibitor nitroxoline and its derivatives can block extracellular matrix degradation, exerting broad-spectrum inhibitory effects on the invasion and metastasis of solid tumors like gastric and colorectal cancers, offering advantages in both subtype specificity and tumor type adaptability [339]. The natural product cycloastragenol (CAG) targets CTSB. By inhibiting CTSB-mediated MHC-I degradation, it effectively promotes tumor antigen presentation. Combined with a PD-1 antibody, it significantly enhances the tumor-killing activity of CD8+ T cells [278]. CTSS, a key protease in MHC-II antigen presentation, plays a prominent role in tumor immune evasion [340, 341]. Its inhibitor VBY-999 can reduce early brain metastasis burden, and its antibody-conjugated formulation combined with irinotecan can block colorectal cancer cell invasion [342]. CTSK inhibitors AFG-495 and L-235 can simultaneously inhibit bone resorption and tumor proliferation in breast cancer bone metastasis models, providing dual-effect treatment options for bone metastasis-related tumors [343, 344]. The same-class inhibitor odanacatib, previously investigated for osteoporosis, was discontinued due to cardiovascular side effects but provides important references for subsequent drug design [345]. The CTSC inhibitor brensocatib has entered phase III clinical studies. Given the high expression of CTSC in breast cancer and NSCLC, its potential as a cancer therapeutic target has been preliminarily validated [346].
Additionally, monoclonal antibodies targeting cathepsins show unique advantages. For example, the anti-CTSS antibody Fsn0503, combined with irinotecan, inhibits colorectal cancer cell invasion by suppressing extracellular matrix remodeling [347]. Such antibodies can not only directly inhibit protease activity but also exert synergistic anti-tumor effects via antibody-dependent cell-mediated cytotoxicity (ADCC), providing new options for patients intolerant to chemotherapy.
Conclusions and future perspectives
LDCD, as an emerging mode of cell death, has seen substantial progress in understanding its initiation, execution, and regulatory networks. LMP can trigger multiple downstream pathways, including apoptosis, ferroptosis, pyroptosis, and ICD, and can reshape the TME. Targeting LDCD not only directly induces tumor cell death but also sensitizes tumors to radiotherapy and chemotherapy. Existing LMP inducers and nanomedicines have demonstrated antitumor activity in preclinical models and earlyphase clinical trials.
However, several critical challenges remain in translating LDCD from basic research to clinical application. First, how cells choose between the ESCRT-mediated membrane repair pathway and lysophagy, and whether this choice is regulated by the duration or severity of lysosomal damage, remains to be elucidated. Furthermore, the difference in tolerance thresholds to lysosomal damage between normal and tumor cells needs to be quantified (e.g., CQ-induced retinal toxicity). Advances in organoid technology may enable quantitative measurement of lysosomal damage thresholds across different normal and tumor cell types, thereby guiding dose optimization [348]. Second, most LMP inducers have limited efficacy as monotherapy and rely on combination regimens. Although nanomedicines offer advantages, they face challenges such as structural complexity, poor metabolic stability, and difficulties in clinical translation. Third, the development of biomarkers enables patient stratification. As shown in Table 1, serum levels of CTSA and CTSH are significantly elevated in patients with nonsmall cell lung cancer, suggesting their potential as early diagnostic markers [349]. In hepatocellular carcinoma, although serum AFP exhibits high sensitivity, its specificity is limited, often leading to false-positive results. A newly developed ELISA kit for LAPTM4B-35 has been validated in pancreatic cancer clinical studies, providing important experimental evidence and practical feasibility for early serological diagnosis and prognostic assessment [63].
Targeting lysosomes in immune cells to remodel the tumor microenvironment and activate systemic antitumor immunity represents a highly promising research direction. Stromal cells such as TAMs and CAFs exhibit characteristic lysosomal abnormalities and may serve as intervention targets. The E64-DNA nanodevice has been shown to enhance antigen presentation and improve immunemediated tumor killing by targeting cysteine cathepsins in the lysosomes of TAMs [335]. Moreover, LDCD is often accompanied by features of ICD, releasing large amounts of DAMPs. Combining LDCD-inducing strategies with immune checkpoint inhibitors holds promise for synergistic antitumor efficacy.
Current LDCD research is largely focused on solid tumors, with limited exploration in hematological malignancies and refractory cancers. Therefore, it is necessary to broaden the spectrum of cancer types amenable to LDCD, with emphasis on hematological tumors and various refractory subtypes. At present, LDCD-related research and development efforts mainly center on solid tumors such as liver cancer, pancreatic cancer, and colorectal cancer, while studies on hematological tumors remain limited. Crucially, refractory subtypes that urgently need clinical breakthroughs—including undifferentiated tumors, multidrugresistant tumors, and recurrent/metastatic tumors—have not yet become a core focus of LDCD research, which greatly restricts the clinical applicability of this therapeutic approach. Future efforts should focus on tailored research and drug development based on the lysosomal functional characteristics of different cancer types: for hematological tumors such as lymphoma and leukemia, which commonly exhibit high cathepsin activity and lysosomal metabolic dysregulation, more specific LMP inducers should be developed to precisely trigger LDCD in tumor cells; for undifferentiated or multidrug-resistant tumors such as TNBC, advanced melanoma, and platinumresistant ovarian cancer, which rely on highly stable and highly active lysosomes for drug efflux and resistance, strategies that disrupt lysosomal membrane stability or block repair pathways may break drug resistance and specifically induce cell death. Through such targeted development, LDCD has the potential to expand from a solid-tumor-focused therapy into a pancancer treatment modality, offering new therapeutic options for patients with various refractory cancers.
In conclusion, as a novel anticancer strategy, the future of LDCD research requires systematic advancement across multiple dimensions: mechanistic dissection, biomarker development, immune modulation, drug optimization, and expansion of indications. As these challenges are progressively addressed, LDCD-centric therapeutic regimens hold the promise of bringing new hope to cancer patients and ushering in a new era of “precision lysosome modulation” in anticancer therapy.
Acknowledgements
Not applicable.
Abbreviations
- ACD
Accidental cell death
- ADCC
Antibody-dependent cell-mediated cytotoxicity
- ADCs
Antibody-drug conjugates
- AFP
Alpha-fetoprotein
- AKT
Protein kinase B
- ALG-2
Apoptosis-linked gene 2
- ALIX
ALG-2-interacting protein X
- AML
Acute myeloid leukemia
- AMP
Adenosine monophosphate
- AMPK
5’-adenosine monophosphate-activated protein kinase
- Apaf-1
Apoptotic protease activating factor 1
- ASC
Adaptor protein apoptosis-associated speck-like protein containing a CARD
- ASM
Acid sphingomyelinase
- ATTECs
Autophagosome-tethering compounds
- AUTOTACs
Autophagy-Targeting Chimeras
- BAK
Bcl2 homologous antagonist/killer
- BAP31
B-cell receptor-associated protein 31
- BAX
Bcl2associated X protein
- BC
Breast cancer
- Bcl-2
B-cell lymphoma 2
- Bid
BH3-interacting domain death agonist
- BMP
Bis(monoacylglycero)phosphate
- BRD4
Bromodomain-containing protein 4
- CADs
Cationic amphiphilic drugs
- CAFs
Cancer-associated fibroblasts
- CAG
Cycloastragenol
- CALR
Calreticulin
- CaMKII
Ca2 +/calmodulin-dependent protein kinase II
- CAR-T
Chimeric antigen receptor T-cell
- CCL2
Chemokine ligand 2
- CHMP4B
Charged multivesicular body protein 4B
- CMA
Chaperone‑mediated autophagy
- CPTNP
Cell-penetrating transformable peptide nanoparticle
- CQ
Chloroquine
- CRC
Colorectal cancer
- CSCs
Cancer stem cells
- CTLA4
Cytotoxic T-lymphocyte-associated antigen 4
- Cyto C
Cytochrome C
- DAMPs
Damage-associated molecular patterns
- DC
Dendritic cell
- DeoxB7,4
Deoxysappanone B 7,4′dimethyl ether
- ECM
Extracellular matrix
- EGFR
Epidermal growth factor receptor
- EGLN2
Egl-9 family hypoxia-inducible factor 2
- EMT
Epithelialmesenchymal transition
- ER
Endoplasmic reticulum
- ERK
Extracellular signal-regulated kinase
- ESCRT-III
Endosomal sorting complexes required for transport III
- GAS
Group A Streptococcus
- GBM
Glioblastoma multiforme
- GC
Gastric cancer
- GPX4
Glutathione peroxidase 4
- GSDMD-N
Gasdermin D N-terminal
- GSDME
Gasdermin E
- HCC
Hepatocellular carcinoma
- HCQ
Hydroxychloroquine
- HER2
Human epidermal growth factor receptor 2
- HIF-1α
Hypoxia‑inducible factor 1α
- HIF-2α
Hypoxia-inducible factor 2α
- HMA
Hexamethylene amiloride
- HMGB1
High mobility group box 1
- Hsp70
Heat shock protein 70
- ICD
Immunogenic cell death
- IL18
Interleukin18
- IL1β
Interleukin1β
- JNK
C-Jun N-terminal kinase
- KRAS
Kirsten rat sarcoma oncogene
- LAMP1/2
Lysosomal associated membrane protein 1/2
- LAPTM4B35
Lysosomal-associated transmembrane protein 4B-35
- LC3
Microtubule-associated proteins 1A/1B light chain 3
- LDCD
Lysosome-dependent cell death
- LLP
Lysosomal lipid peroxidation
- LMP
Lysosomal membrane permeabilization
- LOX
Lipoxygenase
- LPS
Lipopolysaccharide
- LYTACs
Lysosome-targeting chimeras
- M6PR
Mannose6phosphate receptor
- MAPK
Mitogen-activated protein kinase
- MCL-1
Myeloid cell leukemia-1
- MDR
Multidrug-resistant
- MDSCs
Myeloidderived suppressor cells
- MHCI
Major histocompatibility complex class I
- mHTT
Mutant huntingtin protein
- MLKL
Mixed lineage kinase domain-like protein
- MMPs
Matrix metalloproteinases
- MNPs
Magnetic nanoparticles
- MOMP
Mitochondrial outer membrane permeabilization
- MPTP
Mitochondrial permeability transition pore
- mTORC1
Mammalian target of rapamycin complex 1
- NADPH
Nicotinamide adenine dinucleotide phosphate
- NAMPT
Nicotinamide phosphoribosyltransferase
- NCOA4
Nuclear receptor coactivator 4
- NF-κB
Nuclear factor-kappa B
- NLRP3
NOD-, LRR- and pyrin domain-containing protein 3
- NOXA
Phorbol-12-myristate-13-acetate-induced protein 1
- NPC1
NPC intracellular cholesterol transporter 1
- NSCLC
Non-small cell lung cancer
- OV
Ovarian cancer
- PARP
Poly (ADP-ribose) polymerase
- PC
Pancreatic cancer
- PDAC
Pancreatic ductal adenocarcinoma
- PD-L1
Programmed cell death ligand 1
- PDM
Protein degradation machinery
- PDT
Photodynamic therapy
- PFS
Progression-free survival
- P‑gp
P‑glycoprotein
- PIG3
P53-induced gene 3
- PLA2
Phospholipase A2
- POI
Protein of interest
- PPT1
Palmitoyl-protein thioesterase 1
- PUMA
P53 up-regulated modulator of apoptosis
- RCC
Renal cell carcinoma
- RCD
Regulated cell death
- RIPK1
Receptor-interacting serine/threonine-protein kinase 1
- RIPK3
Receptor-interacting serine/threonine-protein kinase 3
- ROS
Reactive oxygen species
- RTKs
Receptor tyrosine kinases
- SLC40A1/FPN1
Solute carrier family 40 member 1
- SQSTM1/p62
Sequestosome 1
- STAT3
Signal transducer and activator of transcription 3
- TAK1
Transforming growth factor-β-activated kinase 1
- T-ALL
T-cell acute lymphoblastic leukemia
- TAMs
Tumor-associated macrophages
- TF
Transferrin
- TFEB
Transcription factor EB
- TFR1
Transferrin receptor 1
- TGM2
Transglutaminase 2
- TLR7/8
Tolllike receptors 7 and 8
- TME
Tumor microenvironment
- TNBC
Triple negative breast carcinoma
- TNF
Tumor necrosis factor
- Tregs
Regulatory T cells
- TRPML1
Transient receptor potential mucolipin 1
- TSG101
Tumor susceptibility gene 101
- UIO
Ultra-small iron oxide
- ULK1
Unc-51 like autophagy activating kinase 1
- Val-Cit
Valine-citrulline
- V-ATPase
Vacuolar-type H+ -transporting atpase
- VEGF-A
Vascular endothelial growth factor A
- VEGF‑D
Vascular endothelial growth factor D
- VTPA
Virus-spike tumor-activatable pyroptotic agent
- XIAP
X-linked inhibitor of apoptosis protein
Author contributions
L.W., L.Z. and L.L.Z. conceived and supervised the project. Y.L., J.F. and X.D. drafted the manuscript. Z.Y. revised and refined the language of the manuscript. L.W. and L.Z. reviewed and proofread the manuscript and figures. All the authors read and approved the final version of the manuscript.
Funding
This work was supported by grants from the National Natural Science Foundation of China (22277102) and Fundamental Research Funds for the Central Universities (Grant No. 2682026ZTO004).
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yang Li, Jiajie Feng and Xinzhu Dong contributed equally to this work.
Contributor Information
Ling-Li Zheng, Email: zhenglingli@cmc.edu.cn.
Lan Zhang, Email: zhanglanx_9@126.com.
Lei Wang, Email: leiwen000@sina.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.