Autophagy initiation inhibition combined with chemotherapy reverses drug resistance in oral cancer

Boyu Li; Jing Li; Simin Li

doi:10.1007/s12672-026-04695-w

. 2026 Feb 19;17:486. doi: 10.1007/s12672-026-04695-w

Autophagy initiation inhibition combined with chemotherapy reverses drug resistance in oral cancer

Boyu Li ^1,^✉, Jing Li ², Simin Li ³

PMCID: PMC13022154 PMID: 41712124

Abstract

Oral cancer, a common malignancy of the head and neck, remains therapeutically challenging largely due to the frequent development of chemotherapy resistance. Autophagy, a key cellular stress-response pathway, contributes to oral cancer cell survival and drug tolerance under therapeutic pressure. Emerging evidence indicates that targeting the initiation phase of autophagy—particularly when combined with conventional agents such as cisplatin—may help reverse resistance and improve treatment efficacy. In this review, we summarize the molecular mechanisms governing autophagy initiation, highlight key actionable targets, and discuss the synergistic effects observed when autophagy inhibitors are paired with chemotherapeutic drugs. We place particular emphasis on newly developed initiation-stage inhibitors, bioactive natural products, and nanotechnology-enabled formulations that show potential for overcoming chemoresistance in oral cancer. By integrating recent advances, this article aims to provide a mechanistic framework and translational considerations to support the development of more precise therapeutic strategies for chemotherapy-resistant oral cancer.

Keywords: Autophagy initiation inhibition, Oral cancer, Chemotherapy resistance, Cisplatin, Combination therapy, Drug resistance reversal

Introduction

Oral cancer remains a major global health challenge, with high incidence and mortality rates. Despite advances in diagnostic techniques and therapeutic modalities, the overall prognosis for patients with oral cancer has not improved substantially over recent decades. A key clinical hurdle is the frequent emergence of chemotherapy resistance, which markedly compromises the efficacy of standard regimens and contributes to poor outcomes. Chemoresistance is multifactorial, driven by genetic and epigenetic alterations as well as microenvironmental influences that enable tumor cells to evade cytotoxic injury, thereby facilitating disease progression and metastasis. This ongoing challenge underscores the urgent need for novel therapeutic strategies that can overcome chemoresistance and restore tumor sensitivity to chemotherapeutic agents [1].

From a clinical-epidemiological perspective, “chemoresistance” is reflected by the substantial proportion of patients who fail to achieve an objective response and/or experience early progression under standard cytotoxic regimens. In recurrent/metastatic squamous cell carcinoma of the head and neck (a setting that commonly includes oral cavity primaries), a classic platinum–fluorouracil doublet achieved an objective response rate (ORR) of ~ 32%, implying that approximately two-thirds of patients had no objective response (primary refractory disease) under this backbone regimen [2]. Even with regimen optimization, resistance remains frequent: in the phase III EXTREME paradigm, adding cetuximab to platinum/5-FU increased ORR from ~ 20% to ~ 36%, yet median progression-free survival remained measured in months, consistent with rapid emergence of acquired resistance [3]. In the locally advanced setting, induction docetaxel/cisplatin/5-FU (TPF) can yield high initial response rates (e.g., ORR ~ 72% in a pivotal trial), but relapse and treatment-refractory disease are still common clinical trajectories, underscoring the need for mechanism-driven strategies to delay or reverse resistance rather than relying on cytotoxic escalation alone [4].

Among the molecular mechanisms implicated in chemoresistance, autophagy has emerged as a pivotal process with a complex, context-dependent role in cancer biology. Autophagy is a highly conserved lysosome-dependent catabolic pathway that degrades and recycles intracellular components, thereby maintaining cellular homeostasis and enabling adaptation to metabolic stress. In cancer, its functions are stage- and context specific. During tumor initiation, autophagy can be tumor suppressive by clearing damaged organelles and limiting genomic instability. In established tumors, however, it may promote survival and progression by supplying metabolic substrates and facilitating resistance to therapy. This duality is particularly evident during chemotherapy, where autophagy may either contribute to tumor cell death or act as a cytoprotective program that enables cancer cells to withstand chemotherapeutic stress.

Of particular interest is the role of autophagy initiation in modulating chemoresistance. The initiation phase of autophagy involves the formation of the phagophore, a process orchestrated by a core set of autophagy-related proteins including the ULK1 complex and the Beclin 1-ATG14L-VPS34 complex [1]. Targeting the molecular components involved in autophagy initiation presents a promising therapeutic avenue to modulate autophagic flux selectively, potentially sensitizing cancer cells to chemotherapy while minimizing off-target effects [1]. Targeting the initiation machinery (ULK1/Beclin1–VPS34 Complex I) blocks autophagosome biogenesis upstream and may better suppress therapy-induced, cytoprotective autophagy compared with degradation-phase blockade, which mainly leads to autophagosome accumulation and lysosomal stress. Initiation-focused strategies also allow greater mechanistic selectivity (e.g., preferential interference with ATG14L-containing VPS34 Complex I rather than broad lysosomal dysfunction). Accordingly, lysosomal inhibitors (e.g., CQ/HCQ) are discussed as clinically relevant comparators, whereas initiation-selective inhibition is emphasized as a more precise direction for combination therapy. Recent studies in various malignancies have demonstrated that inhibition of autophagy initiation can effectively reverse chemoresistance and enhance the efficacy of chemotherapeutic agents. For example, selective disruption of the Beclin 1-ATG14L interaction impairs VPS34 Complex I formation and autophagy initiation without affecting vesicle trafficking regulated by VPS34 Complex II, offering specificity and reduced toxicity in autophagy-targeted therapy [1, 5]. Furthermore, small molecule inhibitors targeting key kinases involved in autophagy initiation, such as ULK1 and class III PI3-kinase, have shown potent anticancer effects and the ability to overcome drug resistance in preclinical models [6, 7].

In oral cancer, autophagy has been implicated in the development of chemoresistance, although the underlying mechanisms are not yet fully defined. Given the central role of autophagy initiation in sustaining tumor cell survival under therapeutic stress, targeting this early stage of the pathway represents a promising strategy to reverse chemoresistance in oral cancer. Moreover, combining autophagy initiation inhibitors with conventional chemotherapy may produce synergistic antitumor effects by enhancing tumor cell death and improving treatment outcomes. Support for this approach comes from studies in other cancer types, where autophagy inhibition increases sensitivity to chemotherapeutic agents and targeted therapies [7, 8]. In addition, the tumor microenvironment—including hypoxia and bacterial infections—can modulate autophagy and shape chemoresistance, suggesting that autophagy-directed interventions may also influence the broader tumor ecosystem [9, 10].

This review systematically summarizes and analyzes current advances in combining autophagy initiation inhibition with chemotherapy to reverse chemoresistance in oral cancer. We aim to clarify the molecular mechanisms underlying autophagy-associated drug resistance, highlight the therapeutic rationale for targeting autophagy initiation, and discuss emerging pharmacological inhibitors with specificity for key initiation complexes. We further address the prospects and challenges of translating autophagy initiation inhibitors into clinical practice for oral cancer management. By integrating findings from this rapidly evolving field, this review seeks to inform the development of innovative combination regimens to overcome chemoresistance and ultimately improve outcomes for patients with oral cancer.

Molecular mechanisms of chemotherapy resistance in oral cancer

Intracellular mechanisms of cisplatin resistance

Cisplatin exerts its cytotoxic effects primarily through the formation of DNA adducts, which induce DNA crosslinks that disrupt replication and transcription, ultimately triggering apoptosis in tumor cells. However, cancer cells develop resistance to cisplatin through multifaceted intracellular mechanisms that mitigate its efficacy. One major mechanism involves enhanced DNA repair pathways. Resistant cells upregulate nucleotide excision repair (NER) components such as ERCC1 and DNA damage response factors like BCLAF1, facilitating the removal of cisplatin-induced DNA lesions and promoting cell survival [11, 12]. Additionally, alterations in drug transport proteins significantly affect intracellular cisplatin accumulation. Downregulation or mislocalization of copper transporter 1 (CTR1), a key mediator of cisplatin uptake, reduces intracellular drug levels, while overexpression of efflux transporters such as ATP-binding cassette (ABC) family members, including P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRP1, MRP2), promotes drug extrusion [13–15]. Moreover, intracellular detoxification via glutathione (GSH) conjugation catalyzed by glutathione S-transferases (GSTs) neutralizes cisplatin, with resistant cells exhibiting elevated GSH levels and GST activity, thereby diminishing cisplatin cytotoxicity [16–18]. The redox balance is also critical; resistant cells often maintain lower reactive oxygen species (ROS) levels or enhance antioxidant defenses, attenuating cisplatin-induced oxidative stress and apoptosis [19, 20]. Furthermore, alterations in signaling pathways, such as activation of PI3K/Akt and Hedgehog pathways, confer prosurvival signals that inhibit apoptosis and facilitate resistance [21, 22]. Epigenetic modifications and changes in non-coding RNA expression, including lncRNAs like LINC02381, also modulate resistance by regulating drug efflux and DNA repair genes [23]. Importantly, autophagy induction serves as a cytoprotective response to cisplatin-induced stress, promoting survival of resistant cells by degrading damaged organelles and proteins [24, 25]. Mitochondrial adaptations, including altered oxidative phosphorylation and mitophagy, further support resistance by maintaining energy homeostasis and reducing apoptosis [26, 27]. Together, these interconnected intracellular mechanisms constitute a complex resistance network that cancer cells exploit to evade cisplatin-induced cytotoxicity, highlighting the need for therapeutic strategies that simultaneously target multiple resistance pathways to improve treatment outcomes.

Autophagy activation is particularly notable as a cellular stress response that protects cancer cells from cisplatin-induced death. Studies have demonstrated that autophagy inhibitors, when combined with cisplatin, synergistically enhance apoptosis in resistant cancer cells, including nasopharyngeal carcinoma and oral squamous cell carcinoma, by disrupting this protective mechanism [24, 25]. Moreover, autophagy modulates the turnover of proteins involved in drug resistance, such as Exo70, which regulates cisplatin efflux via exocytosis, and its degradation is influenced by autophagy pathways [28]. The interplay between autophagy and redox homeostasis is also critical, as autophagy can regulate intracellular ROS levels, which influence cisplatin sensitivity [19]. Therefore, targeting autophagy in combination with cisplatin chemotherapy represents a promising approach to overcome resistance by disabling a key survival pathway activated in response to drug-induced stress.

Regulation of drug resistance by non-coding RNAs

Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have emerged as pivotal regulators in the development of chemoresistance in oral cancer, particularly through their modulation of autophagy-related genes. Autophagy, a cellular degradation and recycling process, plays a dual role in cancer therapy by either promoting cancer cell survival under stress or facilitating cell death. The dysregulation of ncRNAs influences this balance, thereby affecting the sensitivity of oral squamous cell carcinoma (OSCC) cells to chemotherapy. For instance, lncRNAs act as molecular sponges or scaffolds that modulate the expression of autophagy-related genes, impacting key pathways such as epithelial-to-mesenchymal transition (EMT), apoptosis, and drug efflux, all of which are closely linked to drug resistance mechanisms [29, 30]. Among miRNAs, miR-214 has been specifically implicated in the regulation of autophagy initiation by targeting ULK1, a serine/threonine kinase essential for autophagy induction. By modulating ULK1 expression, miR-214 influences the autophagic flux, thereby contributing to the acquisition of chemoresistance in oral cancer cells. This regulatory axis exemplifies how miRNAs can fine-tune autophagy to promote cancer cell survival in the face of chemotherapeutic stress [29]. Additionally, the interplay between lncRNAs and miRNAs forms complex competing endogenous RNA (ceRNA) networks that further regulate autophagy and drug resistance. For example, certain lncRNAs can sequester miRNAs like miR-214, indirectly affecting ULK1 levels and autophagy activity, thus modulating the chemosensitivity of OSCC cells [31].

Notably, the in vivo “efficiency” of ceRNA regulation is highly context-dependent and constrained by quantitative stoichiometry (relative abundance of the circRNA/lncRNA, the miRNA pool, and the total available target sites), subcellular localization, and binding-site architecture. Quantitative studies indicate that many putative ceRNA interactions may be weak in physiological settings unless the ceRNA is expressed at sufficiently high copy numbers to meaningfully titrate miRNAs [32]. In contrast, only a subset of circRNAs with exceptionally high abundance and/or numerous conserved miRNA binding sites (e.g., archetypal “sponge-like” circRNAs) are likely to exert strong miRNA sequestration effects in vivo [33]. Therefore, for circRNA/ceRNA-mediated ferroptosis pathways reported in OSCC, current evidence more often supports mechanistic plausibility (frequently from gain-/loss-of-function systems) than definitive in vivo effect size sufficient to shift clinical outcomes. To bridge this gap, future work should quantify candidate ceRNAs and cognate miRNAs in patient tissues and liquid biopsy/exosomal fractions, and link their levels to ferroptosis readouts (e.g., SLC7A11/GPX4 axis, lipid peroxidation markers) and treatment response endpoints, using rigor-focused validation frameworks and models closer to human disease (e.g., patient-derived organoids/PDX and spatial profiling) [34].

The clinical relevance of these ncRNA-mediated pathways is underscored by their association with poor prognosis and therapeutic failure in oral cancer patients. Moreover, ncRNAs are frequently encapsulated within extracellular vesicles such as exosomes, facilitating intercellular communication that propagates drug resistance phenotypes within the tumor microenvironment [29, 35]. This highlights the potential of targeting ncRNA-autophagy regulatory networks as a therapeutic strategy to overcome chemoresistance. Furthermore, emerging evidence suggests that manipulating ncRNAs involved in autophagy initiation, including miR-214 and its upstream lncRNA regulators, could restore chemosensitivity and improve treatment outcomes in oral cancer. However, the precise molecular mechanisms and the full spectrum of ncRNAs involved remain to be elucidated, necessitating further research to translate these findings into clinical applications [30, 36]. In summary, lncRNAs and miRNAs, particularly miR-214 through its regulation of ULK1, play critical roles in modulating autophagy and thereby influence the chemotherapeutic response of oral cancer cells. Understanding these regulatory networks offers promising avenues for the development of novel biomarkers and targeted therapies aimed at reversing drug resistance in oral squamous cell carcinoma.

Molecular mechanisms of autophagy initiation and its inhibition strategies

Autophagy initiation complex and key proteins (ULK1, Beclin1, etc.)

The initiation of autophagy is orchestrated by a set of core proteins that form the autophagy initiation complex, with ULK1 and Beclin1 playing pivotal roles in this process. ULK1 (Unc-51 Like Autophagy Activating Kinase 1) functions as a serine/threonine kinase that acts as the core regulator at the earliest stage of autophagy induction. It phosphorylates downstream targets to promote the nucleation and formation of the phagophore, the precursor to the autophagosome. ULK1’s activity is tightly regulated by upstream nutrient-sensing pathways, notably the AMPK and mTOR signaling axes, which modulate autophagy in response to cellular energy status and stress signals. For instance, under energy stress, AMPK activates ULK1 by phosphorylation, while mTOR inhibits ULK1 activity under nutrient-rich conditions, thus finely tuning autophagy initiation [37–39].

Beclin1, a mammalian homolog of yeast Atg6, forms a core component of the class III phosphatidylinositol 3-kinase (PI3K) complex, which is essential for autophagosome nucleation. The Beclin1 complex regulates the generation of phosphatidylinositol 3-phosphate (PI3P), a lipid signaling molecule critical for recruiting downstream autophagy machinery to the phagophore assembly site. Beclin1 interacts with various cofactors such as VPS34 and ATG14L to modulate autophagosome formation. Recent studies have also highlighted Beclin1’s role in alternative autophagy pathways, including Rab9-dependent autophagy, expanding its functional repertoire beyond canonical autophagy [39, 40]. Moreover, Beclin1 is subject to post-translational modifications such as phosphorylation by ULK1, which enhances its activity during mitophagy, a selective form of autophagy targeting damaged mitochondria. This ULK1-mediated phosphorylation of Beclin1 at Ser15 is critical for autophagosome formation at mitochondria-associated membranes (MAMs), underscoring the interplay between these two key proteins in selective autophagy [41].

The dynamic regulation of ULK1 and Beclin1 is evident across various pathological and physiological contexts. For example, in nonmuscle-invasive bladder cancer, downregulation of ULK1 and Beclin1 correlates with higher tumor grade and poor prognosis, highlighting their potential as prognostic markers and therapeutic targets [37]. Similarly, in osteoarthritis, decreased expression of ULK1 and Beclin1 contributes to chondrocyte degeneration, while restoration of their levels via Sirt7 activation promotes autophagy and cellular homeostasis [42]. In metabolic diseases such as non-alcoholic fatty liver disease (NAFLD), compounds like Licochalcone A alleviate hepatic lipid accumulation by inhibiting mTOR and upregulating ULK1/Beclin1/VPS34 pathway, thereby enhancing autophagy [43]. These findings collectively emphasize the central role of ULK1 and Beclin1 in initiating autophagy and regulating cellular responses to stress and disease.

Mechanistically, the ULK1 complex acts upstream to activate the Beclin1-containing PI3K complex, creating a cascade that leads to autophagosome biogenesis. ULK1 phosphorylates Beclin1 and other components, facilitating the recruitment of autophagy machinery to the phagophore site. This hierarchical regulation ensures precise control over autophagy initiation, allowing cells to adapt to varying metabolic and stress conditions. The AMPK/mTOR/ULK1 axis is a recurrent theme in this regulation, where AMPK activation promotes ULK1 activity and autophagy induction, while mTOR acts as a negative regulator [38, 44, 45].

In summary, ULK1 serves as the master kinase that initiates autophagy by phosphorylating downstream targets including Beclin1, which in turn forms a nucleation complex essential for autophagosome membrane formation. Their coordinated activity underlies the initiation phase of autophagy, making them critical nodes for therapeutic intervention in diseases characterized by autophagy dysregulation such as cancer, neurodegeneration, and metabolic disorders. Understanding the molecular interplay between ULK1 and Beclin1, as well as their regulation by upstream signaling pathways, provides valuable insights into autophagy modulation strategies to overcome drug resistance and improve treatment outcomes in oral cancer and other malignancies.

Progress in the development of autophagy initiation inhibitors

The development of autophagy initiation inhibitors has garnered significant attention as a promising strategy to overcome drug resistance in cancer, including oral squamous cell carcinoma. Among such inhibitors, macrolide antibiotics like azithromycin have been repurposed due to their ability to interfere with cytoskeletal protein dynamics, thereby suppressing autophagy. Azithromycin and related macrolides disrupt the actin cytoskeleton, which is crucial for autophagosome formation and trafficking, resulting in impaired autophagic flux. This interference with cytoskeletal dynamics leads to the accumulation of autophagosomes and inhibition of their maturation, thus sensitizing cancer cells to chemotherapeutic agents by preventing the cytoprotective effects of autophagy [46]. The advantage of macrolides lies in their established clinical use and tolerability, which facilitates their repositioning as autophagy inhibitors in combination with chemotherapy.

In addition to repurposed drugs, novel chemical entities have been synthesized to target autophagy initiation more specifically. For example, 1,4-naphthoquinone-based Mannich adducts represent a new class of compounds that induce autophagy disruption and promote tumor cell death. These compounds have been shown to selectively inhibit autophagic flux by blocking the fusion of autophagosomes with lysosomes, leading to autophagic stress and apoptosis in cancer cells. The mechanistic basis involves modulation of key autophagy-related proteins and signaling pathways, such as the PI3K/AKT/mTOR axis, which governs autophagy initiation and progression. By targeting these pathways, 1,4-naphthoquinone derivatives effectively impair the survival mechanisms of tumor cells that rely on autophagy under stress conditions [47]. Their chemical scaffold allows for further optimization to enhance potency and selectivity, making them promising candidates for combination therapies aimed at reversing chemoresistance.

Moreover, recent advances have highlighted the pivotal role of the VPS34 complex, a class III phosphatidylinositol 3-kinase essential for autophagy initiation. Inhibitors targeting the VPS34 complex, particularly those disrupting the interaction between Beclin 1 and ATG14, have been developed to selectively inhibit autophagy without affecting endocytic trafficking. Such selective inhibition is crucial to minimize off-target effects and toxicity. For instance, small molecules identified through NanoBRET assays have successfully disrupted the Beclin 1-ATG14 interaction, thereby inhibiting autophagy initiation and sensitizing tumor cells to chemotherapy [48]. The specificity of these inhibitors underscores the therapeutic potential of targeting protein–protein interactions within the autophagy initiation machinery.

Furthermore, the discovery of ULK1 kinase inhibitors, such as SBI-0206965 and its derivatives, has provided tools to block the earliest steps of autophagy initiation. ULK1 is the most upstream kinase in the autophagy cascade, and its inhibition leads to aberrant autophagosome formation and impaired autophagic flux. Novel dual ULK1/2 inhibitors with improved potency and oral bioavailability have demonstrated synergistic cytotoxicity when combined with chemotherapeutic agents like PARP inhibitors in triple-negative breast cancer models [49]. These findings suggest that targeting ULK1 kinase activity can effectively disrupt autophagy initiation and enhance chemotherapy efficacy.

Collectively, the development of autophagy initiation inhibitors encompasses repurposed macrolides that interfere with cytoskeletal dynamics, novel chemical entities such as 1,4-naphthoquinone Mannich adducts that block autophagic flux, and highly selective inhibitors targeting key autophagy initiation complexes like VPS34 and ULK1. These advances provide a robust framework for combining autophagy initiation inhibitors with conventional chemotherapy to overcome resistance in oral cancer and other malignancies. The ongoing refinement of these inhibitors, focusing on specificity, potency, and pharmacokinetic properties, will be critical for their successful translation into clinical applications [46–49].

Natural products and their derivatives in autophagy regulation

Natural products and their derivatives have garnered significant attention for their ability to modulate autophagy, a critical cellular process involved in maintaining homeostasis and regulating cell survival and death. Several studies have demonstrated that natural compounds can directly or indirectly influence key autophagy-related signaling pathways, such as the PI3K-Akt pathway, to exert anticancer effects and enhance chemotherapy efficacy. For instance, extracts from Rumex dentatus and nano-formulated quercetin have been shown to inhibit autophagy by modulating the PI3K-Akt signaling axis, thereby sensitizing cancer cells to chemotherapeutic agents. This regulatory effect on autophagy is particularly relevant in oral squamous cell carcinoma (OSCC), where autophagy often contributes to chemoresistance and tumor progression. Natural products such as naringenin induce endoplasmic reticulum stress-mediated apoptosis and autophagy in OSCC cells, with autophagy initially serving a pro-survival role but shifting towards promoting cell death upon treatment [50]. Similarly, chrysophanol activates autophagy-related proteins via the PI3K/Akt/mTOR pathway in OSCC cells; inhibition of this autophagy enhances apoptosis, suggesting that autophagy acts as a protective mechanism that can be targeted to improve therapeutic outcomes [51]. Fucoidan, a sulfated polysaccharide derived from brown seaweed, has been reported to enhance cisplatin-induced apoptosis in oral cancer cells by inhibiting the PI3K/AKT pathway, which also influences autophagy regulation [52]. These findings underscore the dual role of autophagy in cancer, where its inhibition or activation by natural products can be leveraged to overcome drug resistance.

Beyond oral cancer, natural products have shown efficacy in modulating autophagy across various cancer types through similar mechanisms. For example, sulforaphane, a bioactive compound from broccoli, induces autophagy and apoptosis in prostate cancer cells by upregulating lysosome-associated membrane protein 2 (LAMP2), which modulates autophagic flux and apoptotic pathways [53]. The flavonoid apigenin has demonstrated the ability to suppress colorectal cancer progression by activating JNK-mediated autophagy via the HMGB1 and beclin 1 axis, highlighting the importance of autophagy modulation in tumor suppression [54]. In drug-resistant hepatocellular carcinoma, derivatives of piperlongumine and ligustrazine inhibit thioredoxin reductase, increase reactive oxygen species (ROS), and induce autophagy through regulation of LC3, beclin-1, and p62, thereby promoting cytotoxicity in resistant cancer cells [55]. These studies illustrate that natural products can target autophagy-related proteins and signaling pathways to reverse chemoresistance and enhance cancer cell death.

Mechanistically, many natural products exert their autophagy-regulating effects by targeting the PI3K-Akt-mTOR signaling pathway, a central regulator of cell growth and autophagy. Inhibition of this pathway by compounds such as falcarindiol leads to induction of autophagy accompanied by apoptosis in OSCC cells, involving MAPK signaling components ERK1/2 and p38 [56]. Similarly, chrysophanol-induced autophagy via PI3K/Akt/mTOR pathway interference illustrates the potential for combination therapies that inhibit autophagy to potentiate apoptosis [51]. Fucoidan’s ability to inhibit PI3K/AKT activation enhances cisplatin-induced apoptosis in oral cancer cells, further supporting the therapeutic potential of targeting this pathway [52]. Moreover, nanoformulations of curcumin have been developed to overcome its poor bioavailability and effectively regulate autophagy-related pathways in liver cancer treatment [57].

In addition to direct modulation of autophagy, natural products often influence related cellular stress responses such as endoplasmic reticulum stress and ROS production, which interplay with autophagy regulation. Naringenin induces intracellular ROS generation, triggering ER stress and autophagy that ultimately lead to apoptosis in OSCC cells [50]. Similarly, the marine-derived compound HDYL-GQQ-495 inhibits autophagy by targeting the autophagy adaptor protein P62, resulting in pyroptosis, a form of inflammatory cell death [58]. These multifaceted mechanisms highlight the complexity of natural product actions on autophagy and their potential to synergize with conventional chemotherapy.

Collectively, these findings demonstrate that natural products and their derivatives, including Rumex dentatus extracts and nano-formulated quercetin, modulate autophagy through key signaling pathways such as PI3K-Akt, thereby enhancing the efficacy of chemotherapeutic agents. By either inhibiting protective autophagy or inducing cytotoxic autophagy, these compounds can overcome drug resistance in oral cancer and other malignancies. Continued research into the molecular mechanisms of natural product-mediated autophagy regulation will facilitate the development of novel combination therapies that improve clinical outcomes in cancer treatment [50–52, 55, 56].

To provide a comprehensive overview of the diverse autophagy initiation inhibitors discussed above, Table 1 summarizes the key characteristics of major inhibitor classes, including synthetic small molecules, repurposed drugs, and natural products. The table consolidates information on their primary molecular targets, mechanisms of action, and therapeutic applications in oral cancer, highlighting the multi-faceted approaches available for targeting autophagy initiation. This systematic comparison facilitates the selection of appropriate inhibitors for combination therapy strategies and underscores the potential of both established and emerging agents in reversing chemoresistance in oral squamous cell carcinoma.

Table 1.

Summary of autophagy initiation inhibitors in oral cancer therapy

Inhibitor type/name	Primary target	Mechanism of action	Key Findings/Applications	Clinical status (oncology)
ULK1 inhibitors (SBI-0206965, MRT68921)	ULK1/ULK2 kinase complex	Blocks phosphorylation of autophagy initiation proteins; prevents phagophore formation	Synergistic with PARP inhibitors in TNBC; oral bioavailability; sensitizes OSCC to chemotherapy	Preclinical research compounds; ULK1/2 target is clinical, but these agents are not
VPS34 inhibitors (SAR405, PIK-III)	Class III PI3-kinase (VPS34) complex	Inhibits PI3P generation; blocks autophagosome nucleation	Effective in both chemosensitive and chemoresistant OSCC models; reduces tumor proliferation	Preclinical; primarily used as tool compounds, with no established oncology phase progression
Beclin1-ATG14L Disruptors	Beclin1-ATG14L protein–protein interaction	Selectively disrupts VPS34 Complex I formation; spares endocytic trafficking	High selectivity with minimal off-target effects; enhanced potency and solubility in newer derivatives	Discovery/preclinical stage; PPI disruptors not yet advanced into formal oncology trials
Azithromycin (Macrolide antibiotic)	Cytoskeletal proteins (Keratin-18, α/β-tubulin)	Disrupts cytoskeletal dynamics; impairs lysosomal trafficking and autophagosome maturation	Clinically approved drug with established safety; oral administration; suppresses tumor growth in xenograft models	Approved antibiotic; oncology use is repurposing-oriented, mainly supported by preclinical evidence
Chloroquine/Hydroxychloroquine	Lysosomal acidification	Inhibits lysosomal function; blocks autophagosome-lysosome fusion; prevents autophagic degradation	Enhances cisplatin-induced apoptosis in nasopharyngeal carcinoma; upregulates miR-129; FDA-approved drugs	Approved drugs; widely evaluated in oncology Phase I/II combination trials as autophagy blockers
Quercetin (Natural flavonoid)	PI3K/Akt signaling pathway	Modulates PI3K/Akt pathway; regulates autophagic flux; induces apoptosis	Improved bioavailability via nano-formulation; enhanced tumor targeting; reduced systemic toxicity	Early clinical experience reported (Phase I); oncology translation limited by formulation/bioavailability
Fucoidan (Marine polysaccharide)	PI3K/AKT pathway	Inhibits PI3K/AKT activation; modulates autophagy regulation; promotes apoptosis	Enhances cisplatin-induced apoptosis in oral cancer cells (SCC-25); natural product with low toxicity	Has entered adjunct clinical evaluation (including Phase II settings) in some cancer populations
Chrysophanol (Natural anthraquinone)	PI3K/Akt/mTOR pathway	Activates autophagy via PI3K/Akt/mTOR; autophagy inhibition enhances apoptosis	Protective autophagy can be targeted to improve therapeutic outcomes in OSCC	Preclinical in oncology; no clear clinical trial phase established for anticancer development
1,4-Naphthoquinone Derivatives	Autophagosome-lysosome fusion	Blocks autophagosome-lysosome fusion; induces autophagic stress and apoptosis	Selective cytotoxicity in OSCC cell lines; favorable pharmacokinetic profile in animal studies	Preclinical lead series; clinical testing status remains undefined for the specific derivatives
FTY720 (Fingolimod)	Sphingosine-1-phosphate signaling	Modulates autophagy and apoptosis; disrupts cancer stem cell properties	Combined with paclitaxel, inhibits cisplatin-resistant OSCC growth; reduces clonogenicity and sphere formation	Approved for MS; explored in early-phase oncology studies, OSCC evidence remains preclinical

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Mechanism of synergistic effect of autophagy initiation inhibition combined with cisplatin chemotherapy

Autophagy inhibition enhances cisplatin-induced apoptosis

Cisplatin (CDDP) is a widely used chemotherapeutic agent effective against various cancers, including oral squamous cell carcinoma (OSCC). However, the development of cisplatin resistance remains a major clinical challenge, often associated with increased autophagy activity in tumor cells. Autophagy, a cellular degradation and recycling process, can function as a cytoprotective mechanism that enables cancer cells to survive chemotherapy-induced stress. Thus, autophagy inhibition has emerged as a promising strategy to sensitize tumor cells to cisplatin by promoting apoptosis.

Although this review primarily emphasizes therapeutic strategies targeting the initiation phase of autophagy, lysosomal inhibitors such as chloroquine (CQ) and hydroxychloroquine (HCQ) are included here as clinically advanced reference compounds with well-established safety profiles. These agents do not inhibit autophagy initiation per se; rather, they block autophagic flux at a late stage by impairing lysosomal acidification, and therefore provide a clinically relevant benchmark to contextualize the therapeutic shift from broad late-stage autophagy blockade toward more selective initiation-phase inhibition. Importantly, CQ/HCQ are also widely used pharmacological tools and potential combination partners, offering a practical framework to evaluate whether multi-node autophagy suppression can mitigate compensatory survival responses and improve cisplatin efficacy in oral cancer. Consistent with this rationale, multiple studies have demonstrated that autophagy inhibitors—including CQ, 3-methyladenine (3-MA), and HCQ—can disrupt cisplatin-induced cytoprotective autophagy and thereby enhance apoptotic cell death. For example, in nasopharyngeal carcinoma cells (HNE1), CQ potentiated cisplatin-triggered apoptosis by upregulating miR-129, which suppresses autophagy and drug-resistance proteins such as P-glycoprotein (P-gp) [59]. Similarly, in lung adenocarcinoma cells, dual inhibition of apurinic/apyrimidinic endonuclease 1 (APE1) and autophagy markedly increased cisplatin-induced apoptosis and helped overcome drug resistance [60]. Collectively, these findings underscore autophagy as a key survival mechanism under cisplatin stress and support autophagy blockade—whether used as a benchmark late-stage comparator or as part of rational combination strategies—as a feasible approach to sensitize tumor cells and improve chemotherapy response.

In OSCC models, cisplatin induces both apoptosis and autophagy, partially mediated through reactive oxygen species (ROS) and the JNK pathway. However, early-stage autophagy inhibition, either pharmacologically or via knockdown of autophagy-related genes like ATG5, did not sensitize cells to cisplatin, suggesting that autophagy’s role in acquired resistance may be context-dependent [61]. Conversely, other studies have reported that autophagy inhibition enhances cisplatin sensitivity in oral cancer by promoting apoptosis. For instance, secretory clusterin (sCLU) promotes oral cancer cell survival by activating autophagy through the AMPK/mTOR/ULK1 pathway, thereby inhibiting apoptosis; targeting sCLU-mediated autophagy could sensitize cells to cisplatin [62].

Natural compounds and traditional medicines that inhibit autophagy have also shown synergistic effects with cisplatin. The Chinese herbal medicine Feiyanning (FYN) inhibits protective autophagy induced by cisplatin in non-small cell lung cancer (NSCLC) cells, enhancing cisplatin cytotoxicity [63]. Similarly, fucoidan, a natural product from brown seaweed, enhances cisplatin-induced apoptosis in oral cancer cells by inhibiting the PI3K/AKT pathway, which is linked to autophagy regulation [52]. Other agents such as methylseleninic acid (MSA) induce selective autophagy that protects lung adenocarcinoma cells from mitochondrial damage; combining MSA with autophagy inhibitors enhances apoptosis and overcomes cisplatin resistance [64].

Mechanistically, autophagy inhibition promotes cisplatin-induced apoptosis by disrupting cellular homeostasis and enhancing DNA damage, mitochondrial dysfunction, and ROS accumulation. For example, the inhibition of SET8 preserves PTEN expression, which restores autophagy and attenuates cisplatin-induced apoptosis in kidney cells, highlighting the complex interplay between autophagy and apoptosis in cisplatin toxicity [65]. Moreover, inhibition of autophagy-related proteins such as Beclin-1 and ATG5 sensitizes cisplatin-resistant cells by promoting apoptotic pathways [66].

In summary, autophagy inhibitors block the cytoprotective autophagy induced by cisplatin, thereby enhancing apoptotic signaling and overcoming chemoresistance in oral cancer and other malignancies. This strategy holds promise for improving cisplatin efficacy and clinical outcomes by combining autophagy inhibition with conventional chemotherapy. Future research should focus on identifying specific autophagy modulators and elucidating the molecular mechanisms linking autophagy and apoptosis in cisplatin resistance.

Impact on cell cycle and oxidative stress levels

Combination strategies that concurrently target cell-cycle regulation and oxidative-stress pathways show promise for overcoming drug resistance in oral cancer and other malignancies. A central mechanism is the induction of checkpoint-specific cell-cycle arrest, which limits tumor proliferation and can sensitize cells to cytotoxic agents. For example, rapamycin, an mTOR inhibitor, selectively suppresses oral cancer cell growth by modulating key cell-cycle regulators, including cyclin D1, p15, p21, and p27, leading to cell-cycle arrest and reduced colony formation. This growth inhibition is accompanied by enhanced caspase-9/3–dependent apoptosis, together with increased autophagy and mitochondrial oxidative stress, which collectively exacerbate DNA damage and promote tumor cell death. Notably, rapamycin also attenuates oncogenic signaling pathways such as MAPK, NF-κB, and Wnt/β-catenin—pathways frequently linked to tumor progression and chemoresistance—thereby further strengthening its antitumor activity [67].

Similarly, the use of statins such as pitavastatin has been shown to induce cell cycle arrest and elevate reactive oxygen species (ROS) levels in triple-negative breast cancer cells, a subtype notorious for chemoresistance and poor prognosis. Pitavastatin triggers autophagy-dependent ferroptosis—a form of regulated cell death characterized by iron-dependent lipid peroxidation—by downregulating glutathione peroxidase 4 (GPx4) and ferroptosis suppressor protein 1 (FSP1). This process involves disruption of the mevalonate pathway and is accompanied by increased oxidative stress, underscoring the role of ROS in mediating tumor cell death. The ferroptotic effect of pitavastatin highlights the therapeutic potential of combining autophagy modulation with oxidative stress induction to overcome resistance mechanisms in aggressive cancers [68]. In parallel, emerging evidence indicates that ferroptosis susceptibility in OSCC can also be shaped by upstream non-coding RNA regulation; currently reported circRNA–ferroptosis axes and their downstream targets are systematically summarized in Table 2, providing a concise reference for integrating ferroptosis-oriented biomarkers into future oxidative stress–based combination strategies.

Table 2.

Reported circRNAs involved in ferroptosis regulation in OSCC and their targets

circRNA	Regulation on ferroptosis	Reported axis / target(s)	Validation models	Key readouts / phenotypes (examples)	Evidence level
circFNDC3B	Inhibits ferroptosis (pro-tumor)	miR-520d-5p → SLC7A11	OSCC cell lines; xenograft reported	↑SLC7A11, ↓lipid peroxidation/ROS; ferroptosis resistance and enhanced malignant behaviors	In vitro + in vivo [139]
circ_0000140	Inhibits ferroptosis; associated with cisplatin (DDP) resistance	miR-527 → SLC7A11	OSCC cell lines (DDP resistance context)	Modulates ferroptosis susceptibility; links ferroptosis suppression to DDP resistance	In vitro [140]
circ-CDK8	Promotes ferroptosis pathway dependence (oncogenic context)	miR-615-5p → SLC7A11	OSCC tissues (paired samples reported) + cell lines	circ-CDK8/miR-615-5p/SLC7A11 axis affects erastin-induced ferroptosis and malignant progression-related phenotypes	Patient samples + in vitro [140]

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Alkaloids such as piperine also exemplify the multifaceted approach of combination therapies targeting cell cycle and oxidative stress. Piperine induces cell cycle arrest at G0/G1 and S phases and promotes apoptosis through mitochondrial dysfunction and ROS generation. It modulates multiple oncogenic pathways including Wnt/β-catenin, STAT3/Snail-EMT, and PI3K/Akt/mTOR, while simultaneously regulating oxidative stress responses via inhibition of NF-κB and activation of Nrf2/Keap1 signaling. These combined effects lead to decreased proliferation, migration, and invasion of cancer cells. Moreover, piperine’s ability to enhance the efficacy of chemotherapeutics and radiotherapy through synergistic mechanisms further supports the rationale for its inclusion in combination regimens aimed at disrupting tumor cell survival and resistance pathways [69].

In preclinical models of rhabdomyosarcoma, SFX-01, a synthetic stabilized sulforaphane complex, has demonstrated the capacity to induce G2 cell cycle arrest and apoptosis while suppressing autophagy. SFX-01 increases intracellular ROS levels, thereby exacerbating oxidative stress and mitochondrial dysfunction, which contributes to tumor cell death. When combined with ionizing radiation, SFX-01 exhibits synergistic antitumor effects both in vitro and in vivo, resulting in greater tumor growth inhibition than either treatment alone. These findings suggest that targeting cell cycle checkpoints and oxidative stress simultaneously can potentiate the efficacy of conventional therapies and may be particularly valuable in managing aggressive and resistant tumors [70].

Collectively, these studies underscore the therapeutic promise of combination strategies that induce cell cycle arrest and elevate oxidative stress to disrupt mitochondrial function and promote tumor cell death. By integrating agents that modulate these pathways, it is possible to overcome chemoresistance and improve treatment outcomes in oral cancer and other refractory malignancies. This approach not only impairs tumor proliferation but also triggers multiple forms of programmed cell death, including apoptosis and ferroptosis, through mitochondrial damage and ROS accumulation, thereby enhancing the overall antitumor response. Importantly, discussing the crosstalk among ferroptosis, apoptosis, and necroptosis is highly relevant to chemoresistance because these death programs share upstream stressors (e.g., mitochondrial dysfunction and ROS) and can compensate for one another when a dominant pathway is genetically or pharmacologically constrained. In practice, tumors that evade caspase-dependent apoptosis may shift toward regulated necrosis (necroptosis) or redox-driven ferroptosis, whereas suppression of lipid peroxidation can conversely re-route cell fate toward apoptotic or necroptotic signaling under sustained stress. Therefore, rational combination designs should consider “death-pathway switching” by incorporating orthogonal biomarkers (e.g., caspase activation for apoptosis, RIPK1/RIPK3/MLKL-axis readouts for necroptosis, and lipid peroxidation/iron-homeostasis markers for ferroptosis) in the same experimental and translational pipelines, enabling mechanism-informed regimens that minimize escape routes underlying chemoresistance.

Inhibition of tumor cell migration and invasion

The inhibition of tumor cell migration and invasion is a critical therapeutic goal in oral squamous cell carcinoma (OSCC), as these processes underlie metastasis and poor clinical outcomes. Combined therapeutic strategies that target autophagy initiation alongside chemotherapy have shown promise in suppressing these malignant behaviors by modulating epithelial-mesenchymal transition (EMT)-related genes, particularly E-cadherin. EMT is a biological process where epithelial cells lose their polarity and adhesion properties, acquiring mesenchymal traits that enhance motility and invasiveness. E-cadherin, a key cell–cell adhesion molecule, is typically downregulated during EMT, facilitating tumor dissemination.

Several studies have demonstrated that combined treatments can restore or upregulate E-cadherin expression, thereby inhibiting migration and invasion of oral cancer cells. For instance, treatment with rapamycin, an mTOR inhibitor that promotes autophagy, selectively inhibited oral cancer cell migration and colony formation, while increasing apoptosis. Mechanistically, rapamycin suppressed oncogenic signaling pathways including MAPK, NF-κB, and Wnt/β-catenin, which are known to regulate EMT and metastasis. This suppression correlated with reduced migratory capacity, indicating that autophagy modulation can indirectly influence EMT markers such as E-cadherin to curb tumor spread [67].

Similarly, melatonin has been shown to inhibit migration and invasion in vincristine-resistant oral cancer cells by modulating microRNAs that affect oncogene expression and drug resistance. Melatonin treatment led to upregulation of miR-34b-5p and miR-892a, which are implicated in apoptosis and may influence EMT-related pathways. The resultant decrease in ABC transporter expression reduced drug efflux and enhanced chemosensitivity, which could synergize with autophagy inhibition to suppress tumor invasiveness [71]. Moreover, melatonin treatment in tongue squamous cell carcinoma cells downregulated EMT markers such as Zeb1 and β-catenin, while upregulating E-cadherin, effectively inhibiting migration. This effect was accompanied by induction of autophagy and apoptosis, suggesting a complex interplay between autophagy regulation and EMT suppression [72].

Natural compounds such as anethole and cinnamaldehyde have also demonstrated anti-migratory effects in oral cancer cells by modulating EMT markers. Anethole treatment inhibited EMT by increasing E-cadherin expression and decreasing mesenchymal markers, alongside inducing apoptosis and autophagy. This was mediated through suppression of NF-κB, MAPK, and Wnt signaling pathways, which are central to EMT regulation [73]. Cinnamaldehyde similarly inhibited invasion and migration by blocking NF-κB translocation and downregulating PI3K-AKT-mTOR pathway components, which are critical in EMT progression [74].

Mechanistically, autophagy appears to regulate EMT and metastatic potential through modulation of signaling pathways such as AKT/mTOR and NF-κB. For example, the ROCK inhibitor Y-27632 suppressed OSCC cell migration by inhibiting the AKT pathway and simultaneously upregulating autophagy, suggesting that enhanced autophagy may counteract EMT-driven migration [75]. Furthermore, circRNAs such as circ-LRP6 promote EMT and autophagy in OSCC cells, with downregulation of circ-LRP6 leading to increased E-cadherin and decreased mesenchymal markers, thereby reducing migration and invasion. Autophagy induction rescued EMT inhibition caused by circ-LRP6 knockdown, highlighting the interdependence of autophagy and EMT in tumor progression [76]. Notably, while circRNAs are increasingly reported as upstream regulators of ferroptosis in several tumor types, circRNA-mediated ferroptosis mechanisms have not yet been directly validated in oral cancer cell lines or patient-derived samples within the studies summarized in this review; thus, the current evidence base in OSCC remains insufficient for quantitative enumeration beyond autophagy/EMT- and chemoresistance-linked circRNAs.

Cordycepin, a natural compound, attenuated migration and invasion of OSCC cells by inducing autophagy-dependent suppression of focal adhesion kinase (FAK) and Akt phosphorylation, as well as matrix metalloproteinases MMP2 and MMP9 activities, which are essential for extracellular matrix degradation during metastasis. Blocking autophagy reversed these effects, confirming that autophagy induction mediates the inhibition of EMT-related migratory pathways [77].

To illustrate the integrated mechanisms underlying the synergistic anticancer effects of autophagy initiation inhibition combined with chemotherapy, we present a comprehensive schematic model (Fig. 1). This model demonstrates how the combination of cisplatin with autophagy initiation inhibitors (such as chloroquine, azithromycin, ULK1 inhibitors, and VPS34 inhibitors) and natural products converges on multiple molecular pathways to overcome drug resistance in oral squamous cell carcinoma. The diagram shows that these therapeutic agents exert their effects through dual mechanisms: first, by modulating upstream nutrient-sensing pathways including AMPK/mTOR and PI3K/AKT/mTOR signaling cascades, and second, by directly targeting the autophagy initiation machinery comprising the ULK1 complex and Beclin1-VPS34 complex. The inhibition of these core autophagy initiation complexes, coupled with the regulatory influence of miR-214 on ULK1 expression, effectively blocks autophagosome formation and prevents the cytoprotective autophagy response typically activated under chemotherapeutic stress. In addition, the model integrates key circRNA-mediated ceRNA networks, in which major circRNAs sponge specific miRNAs to derepress autophagy- and resistance-related target genes, thereby fine-tuning ULK1/Beclin1–VPS34 signaling and intersecting with PI3K/AKT–mTOR and oxidative stress pathways. Consequently, cancer cells experience heightened oxidative stress through ROS accumulation, exacerbated DNA damage, enhanced apoptotic cell death, cell cycle arrest, and suppressed migratory and invasive capabilities. The convergence of these cellular consequences ultimately manifests as reversal of chemoresistance and significantly improved therapeutic outcomes, validating the rationale for combination therapy strategies targeting autophagy initiation in oral cancer treatment.

Fig. 1 — Schematic of how autophagy initiation inhibition combined with cisplatin reverses drug resistance in oral squamous cell carcinoma (OSCC). Autophagy initiation inhibitors (CQ, AZM, ULK1/VPS34 inhibitors) and upstream signaling modulation (AMPK, PI3K/AKT–mTOR) block the ULK1 and Beclin1–VPS34 complexes, thereby preventing autophagosome formation. Major circRNA/miRNA networks are overlaid to illustrate ceRNA-mediated regulation of autophagy-related targets and resistance-associated pathways. Downstream effects include increased ROS and DNA damage, enhanced apoptosis and cell-cycle arrest, and reduced migration/invasion, ultimately improving therapeutic efficacy. Solid arrows indicate activation/progression; perpendicular-ended lines indicate inhibition. CQ, chloroquine; AZM, azithromycin; AMPK, AMP-activated protein kinase; mTOR, mechanistic target of rapamycin; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; ULK1, unc-51 like autophagy activating kinase 1; ATG, autophagy-related protein; VPS34, vacuolar protein sorting 34; ROS, reactive oxygen species; circRNA, circular RNA; miRNA, microRNA; ceRNA, competing endogenous RNA

To provide a comprehensive overview of the diverse autophagy initiation inhibitors discussed above, Fig. 2 summarizes the key characteristics of major inhibitor classes, including synthetic small molecules, repurposed drugs, and natural products. The table consolidates information on their primary molecular targets, mechanisms of action, and therapeutic applications in oral cancer, highlighting the multi-faceted approaches available for targeting autophagy initiation. Synthetic inhibitors such as ULK1/VPS34 inhibitors and Beclin1-ATG14L disruptors offer high selectivity and potency, while repurposed drugs like azithromycin and chloroquine provide the advantage of established clinical safety profiles and immediate translational potential. Natural products including quercetin, fucoidan, and chrysophanol demonstrate favorable safety profiles and can be enhanced through nanoformulation strategies to overcome bioavailability limitations. This systematic comparison facilitates the selection of appropriate inhibitors for combination therapy strategies and underscores the potential of both established and emerging agents in reversing chemoresistance in oral squamous cell carcinoma.

Application of emerging nanotechnologies in autophagy inhibition combined chemotherapy

Nanocarriers enhance drug targeting and bioavailability

Nanocarriers have emerged as a pivotal strategy to enhance the therapeutic efficacy of anticancer agents by improving their targeting specificity and bioavailability, which are critical limitations of conventional chemotherapy. Nanoparticle formulations, including those encapsulating natural compounds like quercetin, have demonstrated significant potential in overcoming these challenges. Quercetin, a flavonoid with known anticancer properties, suffers from poor water solubility and low bioavailability, limiting its clinical application. Nanocarrier-based delivery systems, such as polymeric nanoparticles, lipid-based nanoparticles, and inorganic nanocarriers, have been engineered to encapsulate quercetin, thereby enhancing its stability and solubility. For instance, polymer-based nanoparticles utilizing biodegradable materials can protect quercetin from premature degradation and facilitate controlled release, resulting in prolonged circulation time and improved accumulation at tumor sites. Lipid-based nanocarriers, including solid lipid nanoparticles and nanostructured lipid carriers, further improve drug loading and facilitate lymphatic uptake, bypassing first-pass metabolism and enhancing oral bioavailability. Moreover, surface modifications of nanocarriers with targeting ligands such as peptides, antibodies, or cell membrane coatings enable active targeting to tumor cells, increasing drug concentration at the site of action and minimizing off-target toxicity. Biomimetic nanocarriers, which utilize natural cell membranes for coating, can evade immune clearance and exploit the homing properties of their source cells, providing superior tumor targeting. Additionally, stimuli-responsive nanocarriers that respond to tumor microenvironmental cues like pH, redox potential, or enzymes, allow site-specific drug release, further enhancing therapeutic efficacy while reducing systemic side effects. Clinical and preclinical studies have shown that nanocarrier-mediated delivery of quercetin and other flavonoids results in enhanced anticancer effects, including increased apoptosis, inhibition of proliferation, and suppression of metastasis, compared to free drugs. Importantly, nanocarriers can reduce the toxic side effects typically associated with chemotherapy by enabling lower effective doses and targeted delivery. For example, quercetin-loaded nanocarriers have demonstrated improved pharmacokinetics, with increased maximum plasma concentration (Cmax) and area under the curve (AUC), indicating enhanced bioavailability. These formulations also show reduced hemolysis and improved biocompatibility. The versatility of nanocarriers allows co-delivery of multiple therapeutic agents, enabling synergistic effects and overcoming multidrug resistance. Despite these promising advances, challenges remain in optimizing nanocarrier design, ensuring scalability, and translating these systems into clinical practice. Nonetheless, the integration of nanotechnology with natural anticancer agents like quercetin represents a promising avenue to improve oral cancer treatment outcomes by enhancing drug stability, targeting, and bioavailability while minimizing adverse effects [78–81].

Potential of nanomedicine to regulate autophagy pathways

Nanomedicine has emerged as a promising strategy to precisely modulate autophagy pathways in cancer therapy, particularly through the co-delivery of autophagy inhibitors alongside chemotherapeutic agents. Nanocarriers—such as liposomes, polymeric nanoparticles, mesoporous silica nanoparticles, and metal-based nanostructures—offer unique physicochemical properties that enable targeted, controlled, and synergistic drug release within the tumor microenvironment (TME). This capability is critical for overcoming challenges such as drug resistance, poor tumor targeting, and systemic toxicity that limit conventional chemotherapy. Several studies have demonstrated that nanocarriers can encapsulate both chemotherapeutic drugs and autophagy modulators, such as chloroquine (CQ), hydroxychloroquine (HCQ), or novel small-molecule inhibitors, facilitating their co-delivery to tumor cells with high precision and efficiency [82–84].

The co-delivery of autophagy inhibitors with chemotherapy via nanoplatforms allows for the inhibition of protective autophagy that cancer cells often exploit to survive cytotoxic stress. For example, mitochondria-targeting gold nanoparticles co-loaded with doxorubicin and chloroquine have shown enhanced photothermal-chemotherapy efficacy by simultaneously inducing tumor cell apoptosis and inhibiting autophagy, thereby overcoming treatment resistance [84]. Similarly, mesoporous silica nanoparticles conjugated with hyaluronic acid have been engineered to co-deliver isoginkgetin (an autophagy inducer) and doxorubicin, achieving synergistic autophagic cell death and improved antitumor effects in hepatocellular carcinoma models [85]. These nanocarriers exploit tumor-specific microenvironmental triggers such as acidic pH, high glutathione levels, or enzymatic activity to release their payloads selectively, minimizing off-target effects and systemic toxicity.

Beyond co-delivery, certain nanomaterials intrinsically modulate autophagy. Iron oxide nanoparticles functionalized with carboxyl groups can enhance tumoricidal autophagy via sustained reactive oxygen species (ROS) production, suppressing hepatoma growth without additional autophagy inhibitors [86]. Other nanostructures, such as graphene oxide nanosheets, have been shown to regulate autophagy and apoptosis through modulation of signaling pathways like ATG, MAPK, and Akt, sensitizing cancer cells to chemotherapy [87]. Moreover, nanomedicines can be designed to induce autophagy-enhanced ferroptosis, a non-apoptotic form of cell death, by consuming intracellular glutathione and triggering ferritin degradation, thereby amplifying cancer cell death [88, 89].

The integration of autophagy modulation with other therapeutic modalities via nanomedicine further expands treatment possibilities. Nanoplatforms combining autophagy inhibitors with immunotherapy, phototherapy, or gene therapy have demonstrated synergistic tumor suppression by remodeling the tumor immune microenvironment and enhancing immunogenic cell death [82, 90]. For instance, autophagy activator-loaded peptide nanocarriers have been employed to amplify phototherapy-triggered immune responses against metastatic breast cancer, illustrating the potential of nanomedicine to orchestrate complex therapeutic cascades [91].

Despite these advances, challenges remain in translating autophagy-targeting nanomedicines to clinical practice. Issues such as nanotoxicity, biocompatibility, precise control over drug release kinetics, and reproducibility of nanocarrier synthesis require rigorous investigation [92, 93]. Additionally, the dual and context-dependent roles of autophagy in cancer necessitate careful design to either inhibit or induce autophagy appropriately, depending on tumor type and stage [94]. Quality-by-design approaches and comprehensive preclinical evaluations are essential to optimize nanomedicine formulations for safety and efficacy.

In conclusion, nanocarriers provide a versatile and powerful platform for the precise co-delivery of autophagy inhibitors and chemotherapeutic agents, enabling synergistic modulation of the tumor microenvironment to overcome drug resistance and enhance therapeutic outcomes. Continued interdisciplinary research integrating nanotechnology, cancer biology, and pharmacology will be pivotal in advancing these strategies toward clinical implementation for improved management of resistant cancers, including oral carcinoma.

Preclinical studies and safety evaluation

Preclinical investigations utilizing animal models have provided compelling evidence supporting the safety and efficacy of nanoparticle-based combination therapies targeting autophagy initiation alongside chemotherapy to overcome drug resistance in oral cancer. These studies are critical as they bridge the gap between in vitro findings and clinical application by evaluating pharmacodynamics, pharmacokinetics, and systemic toxicity in vivo. For instance, combination regimens incorporating autophagy modulators such as chloroquine or FTY720 with chemotherapeutic agents like paclitaxel have exhibited synergistic antitumor effects in cisplatin-resistant oral squamous cell carcinoma (OSCC) xenograft models. Specifically, FTY720 combined with paclitaxel significantly inhibited tumor growth compared to monotherapy, accompanied by reduced clonogenicity and sphere-forming ability of resistant OSCC cells, without evident systemic toxicity in treated animals [95]. These findings underscore the potential of autophagy modulation to sensitize resistant tumor cells to chemotherapy in vivo.

Moreover, the use of nanoparticle delivery systems enhances the therapeutic index by improving drug bioavailability, tumor targeting, and reducing off-target effects. Nanoparticles facilitate co-delivery of autophagy inhibitors and chemotherapeutic agents, enabling controlled release and accumulation within the tumor microenvironment, thereby maximizing antitumor efficacy while minimizing systemic adverse effects. For example, studies employing multifunctional microtubule-targeting agents with dual pro-apoptotic and anti-autophagic activities demonstrated potent tumor growth inhibition in animal models, highlighting the feasibility of combining autophagy inhibition with cytotoxic therapy [96]. Additionally, oral administration of autophagy inhibitors such as azithromycin showed effective suppression of tumor growth in xenograft mice by disrupting autophagic flux, with favorable safety profiles and without significant weight loss or organ toxicity [97].

Safety evaluation in these preclinical models typically includes monitoring body weight, hematological parameters, histopathological examination of major organs, and behavioral assessments, all of which have generally indicated good tolerability of combination regimens. Importantly, the modulation of autophagy must be carefully balanced, as autophagy can have dual roles in cancer progression and therapy resistance. Thus, selecting appropriate autophagy inhibitors and dosing regimens is crucial to avoid unintended promotion of tumor survival or toxicity to normal tissues [98, 99].

In summary, preclinical animal studies employing nanotechnology-based combination therapies targeting autophagy initiation alongside chemotherapy have demonstrated promising antitumor efficacy and safety in oral cancer models. These findings provide a strong rationale for advancing such strategies into clinical trials. Future research should focus on optimizing nanoparticle formulations, elucidating precise mechanisms of autophagy modulation in resistant tumors, and comprehensive toxicological assessments to ensure safe translation into clinical practice. The integration of these preclinical insights holds significant promise for improving therapeutic outcomes and overcoming chemoresistance in oral cancer patients.

Preclinical and clinical research progress on autophagy initiation inhibition in reversing drug resistance in oral cancer

In vitro cell lines and animal model studies

In vitro studies using oral squamous cell carcinoma (OSCC) cell lines have demonstrated that combining autophagy inhibitors with cisplatin significantly enhances chemosensitivity by lowering the IC50 values and promoting apoptosis. For example, the use of azithromycin (AZM), a macrolide antibiotic identified as a potent autophagy inhibitor, disrupts cytoskeletal protein dynamics by binding to keratin-18 and α/β-tubulin, thereby blocking autophagic flux in cancer cells. This inhibition of autophagy sensitizes tumor cells to chemotherapy-induced apoptosis, as autophagy often serves as a survival mechanism under chemotherapeutic stress. In OSCC models, the combination of AZM with cisplatin could potentially reduce the effective dose of cisplatin needed to induce cell death, thus mitigating toxicity while overcoming resistance mechanisms [97]. Similarly, studies with natural compounds such as extracts from Rumex dentatus L. have shown synergistic effects with cisplatin in tongue carcinoma cell lines (HNO97). The combination not only inhibited proliferation more effectively than cisplatin alone but also induced cell cycle arrest and apoptosis while reducing autophagy markers. Network pharmacology analysis suggested that this synergy involves key pathways like PI3K-Akt signaling and EGFR tyrosine kinase inhibitor resistance, which are critical in OSCC chemoresistance [100]. Furthermore, novel synthetic compounds such as Mannich adducts derived from 1,4-naphthoquinones have been found to induce autophagy followed by late apoptosis in OSCC cell lines. Compound 6a, in particular, showed selective cytotoxicity and induced autophagic cell death, which was reversed by autophagy inhibitors, confirming autophagy’s role in its mechanism. These findings highlight the potential of targeting autophagy to sensitize OSCC cells to chemotherapy [101].

Animal xenograft models further validate the efficacy of combining autophagy inhibition with chemotherapy in vivo. Oral administration of AZM in xenografted mice suppressed tumor growth while inhibiting autophagy in tumor tissues, demonstrating that autophagy inhibition can potentiate chemotherapy effects in a physiological context. This model confirms that the disruption of lysosomal trafficking and cytoskeletal dynamics by AZM translates into tangible antitumor activity and resistance reversal in vivo [97]. Additionally, other cancer models, such as bladder cancer xenografts, have shown that combining autophagy-inducing compounds with chemotherapeutic agents like gemcitabine enhances tumor suppression and overcomes drug resistance. For instance, the ursolic acid molecular hybrid UA4, when combined with gemcitabine, synergistically killed both naïve and gemcitabine-resistant bladder cancer cells in vitro and significantly inhibited tumor growth in athymic mice. This combination also increased reactive oxygen species and mitochondrial dysfunction, mechanisms that may be relevant to OSCC as well, supporting the concept that targeting autophagy-related pathways can improve chemotherapy outcomes [102]. Collectively, these in vitro and in vivo studies underscore the promising strategy of combining autophagy inhibitors with cisplatin chemotherapy to overcome drug resistance and enhance apoptosis in oral cancer, paving the way for translational research and clinical application.

Current status and challenges of clinical research

The clinical research landscape concerning autophagy initiation inhibition combined with chemotherapy for reversing drug resistance in oral cancer remains in its nascent stages, with limited clinical data available to conclusively demonstrate safety and efficacy. Most existing studies are preclinical or in vitro analyses, highlighting the potential of various autophagy modulators, such as azithromycin (AZM), curcumin analogs, and novel compounds, to sensitize oral cancer cells to chemotherapy agents like cisplatin. For instance, AZM has been identified as a potent autophagy inhibitor that disrupts cytoskeletal protein dynamics, thereby blocking autophagic flux and suppressing tumor growth in xenograft models [97]. Similarly, the combination of a curcumin analog (PAC) with cisplatin has shown synergistic effects in oral cancer cell lines by enhancing apoptosis and autophagy, leading to a significant reduction in cisplatin’s IC50 and improved cytotoxicity [103]. Despite these promising preclinical results, translation into clinical practice is hindered by the lack of robust clinical trials that evaluate these combinations in patients. The safety profiles, optimal dosing regimens, and long-term outcomes remain largely uncharacterized in clinical settings. Moreover, the complexity of autophagy’s dual role in cancer—sometimes promoting survival and at other times facilitating cell death—adds to the challenge of effectively targeting this pathway in patients without unintended consequences.

Optimizing drug dosages and designing effective combination regimens represent critical areas for future clinical research. The pharmacokinetics and pharmacodynamics of autophagy inhibitors, when used alongside conventional chemotherapeutics, need thorough investigation to establish synergistic effects while minimizing toxicity. For example, the naphthoquinone derivative 6a demonstrated selective autophagy induction followed by apoptosis in oral squamous cell carcinoma models, with a favorable pharmacokinetic profile and tolerability in animal studies, suggesting potential for dose optimization in clinical trials [101]. Additionally, natural compounds such as phenolic aglycones from Rumex dentatus L. have exhibited synergistic anticancer effects with cisplatin by modulating multiple signaling pathways, including PI3K-Akt and EGFR resistance pathways, underscoring the importance of multi-targeted approaches in combination therapy [100]. The challenge lies in translating these multi-faceted molecular interactions into standardized, reproducible treatment protocols that can be rigorously tested in clinical trials.

Furthermore, the heterogeneity of oral cancer and the variability in patient responses necessitate personalized treatment strategies that consider molecular biomarkers and resistance mechanisms, such as the involvement of miR-214 and ULK1 in modulating autophagy and chemoresistance [104]. Long non-coding RNAs (lncRNAs) have also emerged as key regulators of drug resistance via autophagy and epithelial-mesenchymal transition processes in head and neck squamous cell carcinoma, providing potential targets for therapeutic intervention and biomarkers for patient stratification [36]. However, integrating these molecular insights into clinical trial design requires extensive validation and standardization.

In summary, while preclinical evidence strongly supports the potential of autophagy initiation inhibition combined with chemotherapy to overcome drug resistance in oral cancer, the current clinical data remain limited. Addressing the challenges of drug dosing optimization, combination regimen design, patient selection, and safety evaluation through well-structured clinical trials is essential. This will pave the way for establishing effective, personalized therapeutic strategies that harness autophagy modulation to enhance chemotherapy efficacy and ultimately improve patient outcomes.

Future research directions and application prospects

Development of multi-target combination therapy strategies

Multidrug resistance (MDR) remains a formidable obstacle in oral squamous cell carcinoma (OSCC), frequently resulting in treatment failure and recurrence. Mechanistically, MDR arises from intertwined genetic/epigenetic changes and stress-adaptive programs, among which autophagy plays a central and context-dependent role. As a lysosome-dependent degradation pathway, autophagy can enhance tumor cell fitness under therapeutic pressure by recycling damaged organelles and proteins, sustaining energy homeostasis, limiting toxic stress accumulation, and mitigating apoptosis. This adaptive buffering allows cancer cells to better tolerate cytotoxic insults from chemotherapy and immunotherapy, thereby substantially contributing to MDR in oral cancer [98, 99, 105].

Accordingly, multi-target combination strategies that integrate autophagy modulation with conventional chemotherapy and immunotherapy provide a rational route to overcome MDR. Pharmacologic inhibitors such as chloroquine and azithromycin can disrupt autophagic flux and sensitize resistant OSCC cells to cisplatin and paclitaxel, with chloroquine impairing lysosomal acidification and azithromycin perturbing cytoskeletal dynamics required for lysosomal trafficking, thereby amplifying apoptosis when combined with chemotherapy [97, 106]. In the tumor microenvironment, autophagy inhibition may further reshape immune cell infiltration by enhancing tumor antigen availability and immunogenic stress signaling, thereby facilitating dendritic-cell priming and promoting the recruitment and/or functional reinvigoration of CD8 + cytotoxic T cells. In parallel, autophagy blockade has been reported to influence myeloid compartments, with potential reductions in immunosuppressive populations (e.g., MDSCs/TAM-like phenotypes) and a shift toward a more pro-inflammatory milieu, which collectively may improve the responsiveness to immunochemotherapy in oral cancer [107, 108]. In addition, multi-target natural agents and pathway- or RNA-axis–focused approaches further illustrate how coordinated regulation of autophagy, apoptosis, and stress signaling can reverse resistance, while novel combinations such as the curcumin analog PAC plus cisplatin may lower the effective cisplatin dose and reduce toxicity without sacrificing efficacy [71, 103, 106, 109].

Biomarker screening and precision therapy

The identification and application of autophagy-related biomarkers have emerged as a promising strategy for predicting chemoresistance and monitoring therapeutic efficacy in oral cancer and other malignancies. Among these, the miR-214/ULK1 regulatory axis has been shown to play a critical role in autophagy-mediated drug response. Elevated miR-214 expression and suppressed ULK1 levels in oral squamous carcinoma cells prior to chemotherapy suggest maintenance of a chemoresistant phenotype through autophagy inhibition, whereas chemotherapy-induced downregulation of miR-214 and concomitant upregulation of ULK1 and other autophagy-related genes indicate activation of autophagy as an adaptive stress response. Functional studies further demonstrate that ULK1 suppresses tumor cell viability and invasion while promoting apoptosis, effects counteracted by miR-214, positioning miR-214 as an early prognostic biomarker and ULK1 as a potential therapeutic target for overcoming drug resistance in oral cancer [104].

Beyond miR-214 and ULK1, multiple autophagy-associated molecules, including IFNG, circRNAs, and lncRNAs, have been implicated as biomarkers of chemoresistance and treatment response across cancer types. IFNG correlates with immune checkpoint markers and cisplatin sensitivity, supporting its role in predicting immunochemotherapeutic outcomes [110], while circRNAs (e.g., circ-VPS13C) and lncRNAs (e.g., HAR1A) regulate autophagy-related pathways and modulate cisplatin resistance, highlighting their utility in precision oncology [111, 112].

Notably, from a clinical detection standpoint in OSCC, the circRNAs with the most immediate translational value are those validated directly in patient-derived, minimally invasive specimens and/or repeatedly linked to clinicopathological parameters in clinical cohorts. For example, salivary hsa_circ_0001874 and hsa_circ_0001971 have been reported as diagnostic candidates in OSCC cohorts (saliva-based testing), supporting feasibility for non-invasive screening/triage. In addition, plasma exosome-derived circRNAs—such as exosomal hsa_circRNA_047733—have been evaluated for clinically relevant stratification (e.g., preoperative prediction of lymph node metastasis), aligning with real-world decision points in OSCC management. Tissue-validated circRNAs, including hsa_circ_0008309 and circ_0086414, have also been associated with tumor stage and/or nodal status in patient samples, suggesting utility as adjunct biomarkers when biopsy material is available and for integrating circRNA readouts into risk models.

Importantly, clinical experience with autophagy inhibitors such as hydroxychloroquine underscores the necessity of biomarker-guided patient stratification to achieve therapeutic benefit [113]. Combined biomarker panels incorporating autophagy markers (LC3-II, Beclin 1), cancer stem cell markers, and immune-related signatures further improve prediction of treatment response [110, 114]. Collectively, integration of autophagy-related biomarkers into clinical trial design and therapeutic decision-making offers a feasible path toward precision therapy, enabling more effective combination strategies to overcome chemoresistance and improve patient outcomes.

Design of novel autophagy modulators and innovations in drug delivery systems

The development of novel autophagy initiation inhibitors with high efficacy and low toxicity, combined with advanced nanotechnology-based drug delivery systems, represents a promising strategy to overcome chemoresistance in oral cancer. Given the dual role of autophagy in cancer—often supporting tumor cell survival under therapeutic stress—selective inhibition of autophagy initiation may enhance chemosensitivity while minimizing adverse effects on normal tissues. Recent progress demonstrates that nanomaterials can be rationally engineered to both modulate autophagy pathways and act as precise delivery vehicles, thereby improving the therapeutic index and reducing systemic toxicity [115, 116]. Various nanocarriers, including polymeric nanoparticles, liposomes, and metal-based systems, have been developed to encapsulate autophagy inhibitors, enabling tumor-targeted delivery and controlled release in response to microenvironmental cues such as pH or redox conditions [117, 118].

Notably, beyond conceptual delivery designs, several ferroptosis-oriented nanoplatforms have already demonstrated in vivo feasibility in oral cancer models. For example, a supramolecular “photosensitizer–inducer” nanodrug co-assembling chlorin e6 with the system Xc⁻ inhibitor erastin enhanced ROS amplification, relieved hypoxia, and achieved significant tumor growth suppression in CAL-27 oral tongue squamous cell carcinoma xenografts [119]. In addition, a tumor-targeted hollow mesoporous MnO₂ nanozyme system (surface-modified with targeting motifs) enabled stimulus-triggered release of the GPX4 inhibitor RSL3, coupled with intratumoral redox remodeling (ROS amplification and GSH depletion), producing robust antitumor efficacy in OSCC-bearing mice [120]. These representative OSCC/OTSCC animal studies support the practicality of nano-enabled ferroptosis induction and provide a concrete foundation for advancing combination regimens toward translational evaluation.

Beyond improving drug accumulation at tumor sites, nanotechnology enables co-delivery of chemotherapeutic agents and autophagy inhibitors to achieve synergistic antitumor effects and overcome multidrug resistance [121, 122]. Surface functionalization with targeting ligands, such as transferrin or aptamers, further enhances cellular uptake specificity via receptor-mediated endocytosis, particularly in EGFR- or CD44-overexpressing cancer cells [123, 124]. Importantly, nanocarrier-based delivery of autophagy initiation inhibitors must account for specific molecular targets, including ULK1 complex components and Beclin-1 interactions, to effectively block autophagosome formation without disrupting basal autophagy required for normal cell homeostasis [125, 126]. Emerging nanoplatforms also permit real-time monitoring of autophagy status through imaging modalities, enabling personalized treatment optimization [127], while stimuli-responsive systems coupled with photothermal or photodynamic therapy provide additional opportunities to enhance tumor cell death by locally modulating autophagy [128, 129]. Despite these advances, challenges related to biocompatibility, stability, immune evasion, and clinical translation remain, underscoring the need for continued interdisciplinary efforts to advance autophagy-targeted nanotherapeutics toward clinical application.

Clinical translation and construction of personalized treatment strategies

Personalized clinical translation of autophagy initiation inhibition plus chemotherapy in oral cancer requires integrating molecular biomarkers with tumor heterogeneity to guide patient-specific regimens. In OSCC, miR-21 is a key regulator linked to aggressiveness and chemoresistance through multiple oncogenic pathways and autophagy/apoptosis control, making it a useful prognostic/predictive marker and a potential therapeutic target [130]. In parallel, actionable targets such as TGM2 and LC3 support rational combinations, and preclinical evidence indicates that initiation inhibitors (e.g., MRT68921, SAR405) can synergize with chemotherapy in both chemosensitive and resistant OSCC models [131]. Chemoresistance is further shaped by stemness and signaling-network dependencies, motivating multi-node precision strategies. KLF4-associated stemness may be therapeutically countered by metabolic modulators such as metformin to enhance cisplatin responses [132], while DDX27 and AXL represent additional resistance-related targets for tailored combinations [133, 134]. Patient-derived functional testing platforms (e.g., 3D spheroids-on-a-chip) can prioritize individualized regimens [135], and targeting the frequently activated AKT/mTOR axis—currently under clinical evaluation—may further strengthen personalized combinations with autophagy inhibition and chemotherapy [136].

With respect to bedside readiness, clinical trials explicitly designed around “ferroptosis induction + chemotherapy” in head and neck tumors (including OSCC) remain scarce. However, mechanistically proximate strategies that sensitize tumors to oxidative stress by inhibiting system Xc − (xCT/SLC7A11)—a core anti-ferroptotic node—have already entered early-phase clinical testing in other solid tumors. For example, sulfasalazine has been evaluated in combination with cisplatin in CD44v-expressing, cisplatin-refractory advanced gastric cancer [137]. In addition, salazosulfapyridine (SASP; an xCT inhibitor) has been tested together with cisplatin-based chemotherapy in an open-label phase I setting [138]. Collectively, these early-phase precedents support the clinical feasibility of pairing ferroptosis-sensitizing redox interventions with platinum chemotherapy, while underscoring the unmet need for OSCC/HNSCC-dedicated trials incorporating ferroptosis-relevant pharmacodynamic biomarkers (e.g., SLC7A11/xCT, GPX4 activity surrogates, and lipid peroxidation signatures) to confirm on-target engagement and minimize “mechanism drift” during translation.

To overcome the current limitation of clinical evidence, future translation should adopt pragmatic strategies that enable efficient human data generation. These include early-phase combination studies using repurposed autophagy inhibitors with known safety profiles, window-of-opportunity neoadjuvant designs allowing paired tumor sampling for pharmacodynamic validation, and prospective biomarker-integrated trial frameworks to enrich responsive patient subsets. In parallel, multicenter real-world registries could complement interventional trials by systematically capturing safety, feasibility, and outcome data, thereby accelerating the transition of autophagy-targeted strategies from bench to bedside.

Conclusion

The challenge of chemoresistance in oral cancer complicates clinical management and patient outcomes, with autophagy initiation identified as a key therapeutic target. Research shows that inhibiting this process can enhance the efficacy of chemotherapeutic agents like cisplatin, promoting apoptosis and reducing tumor aggressiveness. However, the complex roles of autophagy necessitate precise modulation to avoid adverse effects. Integrating natural products and advanced drug delivery systems provides innovative strategies to address chemoresistance. Despite promising preclinical findings, clinical applications are still developing, requiring tailored multi-targeted approaches and rigorous molecular studies to improve patient outcomes through better understanding of autophagy’s role in cancer. Overall, enhancing insights into autophagy initiation in oral cancer could lead to more effective, personalized treatments, improving survival rates and quality of life for patients.

Author contributions

BL conceptualized and designed the study. JL did the literature research, reviewed and revised the manuscript. SL provided critical revision of the manuscript for important intellectual content. BL drafted the manuscript and supervised the research. All authors reviewed and approved the final version.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

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.

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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.

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PERMALINK

Autophagy initiation inhibition combined with chemotherapy reverses drug resistance in oral cancer

Boyu Li

Jing Li

Simin Li

Abstract

Introduction

Molecular mechanisms of chemotherapy resistance in oral cancer

Intracellular mechanisms of cisplatin resistance

Regulation of drug resistance by non-coding RNAs

Molecular mechanisms of autophagy initiation and its inhibition strategies

Autophagy initiation complex and key proteins (ULK1, Beclin1, etc.)

Progress in the development of autophagy initiation inhibitors

Natural products and their derivatives in autophagy regulation

Table 1.

Mechanism of synergistic effect of autophagy initiation inhibition combined with cisplatin chemotherapy

Autophagy inhibition enhances cisplatin-induced apoptosis

Impact on cell cycle and oxidative stress levels

Table 2.

Inhibition of tumor cell migration and invasion

Fig. 1.

Fig. 2.

Application of emerging nanotechnologies in autophagy inhibition combined chemotherapy

Nanocarriers enhance drug targeting and bioavailability

Potential of nanomedicine to regulate autophagy pathways

Preclinical studies and safety evaluation

Preclinical and clinical research progress on autophagy initiation inhibition in reversing drug resistance in oral cancer

In vitro cell lines and animal model studies

Current status and challenges of clinical research

Future research directions and application prospects

Development of multi-target combination therapy strategies

Biomarker screening and precision therapy

Design of novel autophagy modulators and innovations in drug delivery systems

Clinical translation and construction of personalized treatment strategies

Conclusion

Author contributions

Funding

Data availability

Declarations

Ethics approval and consent to participate

Competing interests

Footnotes

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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