Dietary modulation of CMA: implications for cancer prevention and therapy

Abstract

Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that links nutrient availability to intracellular proteostasis through the targeted turnover of selective cytosolic proteins. Through this selective control of protein quality, CMA participates in the regulation of metabolic adaptation, cellular homeostasis, and stress responses.

CMA is highly responsive to nutritional cues, including caloric restriction (CR), fasting, and changes in macronutrient composition, positioning this pathway as a key mediator of cellular adaptation to metabolic stress. In cancer, CMA displays context-dependent functions that influence tumor metabolism, genomic stability, and survival under adverse microenvironmental conditions. These dual roles suggest that dietary modulation of CMA may shape tumor initiation and progression through effects on cellular proteostasis and metabolic plasticity.

In this review, we summarize current knowledge on the molecular mechanisms by which nutritional signals regulate CMA and discuss the physiological implications of nutrition-driven CMA modulation for cancer prevention and therapy.

Summary

Chaperone-mediated autophagy (CMA) links nutrient sensing to tumor metabolic plasticity, driving context-dependent cancer progression.

Abstract figure.

Overview of dietary components differentially regulating CMA, impacting malignant transformation and tumor metabolism. Created in BioRender. Madrigal Matute, J. (2026) https://BioRender.com/qz4a564

1. Introduction

The maintenance of cellular proteostasis is a fundamental requirement for cell survival and functional integrity (1). Among the mechanisms that sustain this balance in eukaryotic cells, two major intracellular degradation pathways can be identified: the ubiquitin–proteasome system (UPS) and lysosome-based autophagy (Figure 1). Autophagy plays a central role in mediating the lysosomal degradation and recycling of intracellular components promoting cellular homeostasis, renewal, and metabolic efficiency (2, 3). The UPS targets ubiquitinated short-lived proteins for degradation through the coordinated action of E3 ubiquitin ligases and deubiquitinating enzymes (2). Long-lived proteins and intracellular components, including damaged organelles as well as functional cellular constituents that can be recycled to support metabolic adaptation, are mainly turned over through lysosomal autophagy pathways (4). Three major forms of autophagy coexist in eukaryotic cells: macroautophagy, microautophagy and CMA. While macroautophagy involves the sequestration of cytosolic components within double-membrane vesicles that are subsequently delivered to lysosomes, endosomal microautophagy occurs through direct invagination of the endolysosomal membrane to engulf cytosolic material (5–7). In contrast, proteins targeted for degradation via CMA are individually recognized by a group of chaperones and co-chaperones, including cytosolic HSC70, and subsequently degraded through the lysosomal pathway (8).

Figure 1.

Major proteostasis pathways in eukaryotic cells. Protein homeostasis is maintained through the coordinated action of the ubiquitin–proteasome system (UPS) and lysosome-based autophagy. The UPS degrades ubiquitinated short-lived proteins through the proteasome, whereas autophagy mediates the lysosomal turnover of long-lived proteins, protein aggregates, and damaged organelles. Three major autophagic pathways coexist in eukaryotic cells: macroautophagy, microautophagy, and CMA. Crosstalk between the UPS and autophagy is mediated in part by p62/SQSTM1, which links ubiquitinated cargo to both degradation systems and contributes to cellular proteostatic balance. Created in BioRender. Madrigal Matute, J. (2026) https://BioRender.com/qz4a564

A molecular interplay exists between autophagy and the ubiquitin–proteasome system, as both pathways share the multifunctional adaptor protein p62/SQSTM1, which acts as a selective receptor for ubiquitinated cargo and coordinates the proteostatic balance between proteasomal and lysosomal degradation pathway (9, 10). In certain cell types, such as cardiomyocytes, defective autophagy leads to the accumulation of p62, which binds ubiquitinated proteins and promotes their aggregation, thereby impairing proteasomal degradation and highlighting how disruption of autophagy system compromises cellular function and survival (11). Conversely, inhibition of UPS in prostate cancer cells by proteasome inhibitors such as NPI-0052 also impacts autophagy. It induces autophagosome formation, increases the conversion of LC3-I to LC3-II and enhances autophagic flux as a compensatory response to impaired proteasomal degradation (12).

CMA protein degradation is based on three fundamental components: 1) the cytosolic chaperone HSC70, which recognizes 2) KFERQ-like motifs in substrate proteins, and 3) the lysosomal membrane protein LAMP2A (13). At the lysosomal membrane, LAMP2A (the rate-limiting component of CMA) binds the substrate protein, forming a translocation complex that facilitates the transport of the substrate into the lysosomal lumen (14). This LAMP2A multimerization process at the lysosomal membrane is a key step in CMA. LAMP2A is initially present as a monomer and reorganizes into higher-order complexes upon substrate binding and delivery by HSC70 and other co-chaperones. The functional channel mediates the import of target proteins into the lysosomal lumen for degradation. The multimerization process is tightly regulated by the membrane microenvironment, particularly cholesterol-rich lipid microdomains, which influence LAMP2A availability, stability, and assembly and can be modulated by a fat- and cholesterol-rich diets (15, 16). In addition to cytosolic HSC70, the lysosomal chaperone HSC70-Lys completes the translocation process by unfolding the substrate protein and supporting the disassembly of the translocation complex (17).

Historically, both macroautophagy and CMA emerged from observations that lysosomal self-digestion is tightly coupled to nutrient availability (18, 19). Early ultrastructural studies in liver described the appearance of cytoplasmic material within lysosomal/vacuolar compartments under nutrient/hormonal cues that mimic starvation, laying the groundwork for what later became known as macroautophagy (18). These early observations anticipated a broader physiological concept: nutrient availability is a central regulator of metabolic adaptation and immune function. Dietary patterns, caloric intake, and nutrient quality influence the “cancer-immune set point”, a framework describing the dynamic balance between factors that promote or restrain anti-tumor immunity and determine disease susceptibility, progression, and therapeutic response (20). In this context, autophagy acts as a central integrator of nutrient sensing, immune regulation, and tumor biology.

Through its central role in cellular proteostasis, CMA has gained attention in cancer research due to its context-dependent dual role in tumor biology (13). In non-transformed and healthy cells, CMA acts as a quality control mechanism that limits oncogenic transformation by degrading damaged, misfolded, or functionally aberrant proteins, including some with oncogenic potential (21–23). This tumor-suppressive function is particularly relevant during early stages of transformation, where CMA helps preserve genomic integrity and suppresses pro-inflammatory and pro-tumorigenic signaling pathways (13). However, once malignant transformation has occurred, many tumor cells exhibit elevated CMA activity, which supports cancer cell survival by sustaining high metabolic plasticity, promoting resistance to oxidative stress, and preventing apoptosis under unfavorable conditions such as nutrient deprivation or hypoxia (13).

This apparent duality raises a central unresolved question in the field: should CMA be therapeutically enhanced or inhibited in cancer? While current evidence might suggest a context-dependent answer, this dichotomy remains incompletely understood. In this review, we aim to critically examine how nutritional and metabolic inputs shape CMA activity across different tumor contexts, with the goal of clarifying whether CMA modulation can be harnessed in a mechanistically informed manner.

2. CMA at the crossroads of tumor metabolism and proteostasis

Dietary inputs represent one of the most pervasive systemic modulators of tumor metabolism, shaping nutrient availability, hormonal signaling, and cellular stress responses that ultimately influence cancer cell fitness (24). In this landscape, CMA emerges as a context-dependent regulator of proteostasis and metabolic plasticity, rather than a unidirectional driver of tumor progression or suppression (13).

CMA as a regulator of cellular energetics

Cellular energetic flux is a critical determinant of tumor cell fitness, as many cancer types depend on the precise regulation of metabolic pathway selection to sustain proliferation, maintain redox balance, and ensure survival under fluctuating nutrient conditions (25). In this context, CMA contributes to the dynamic remodeling of metabolic enzyme availability influencing how tumor cells allocate energetic resources and regulate carbohydrate and lipid metabolism (3, 26). CMA degrades lipogenic enzymes to prevent lipid accumulation (27, 28), modulates lipogenic pathways (3, 29), and ensures efficient lipolysis through the degradation of PLIN2 and PLIN3 (26). In addition, CMA contributes to mitochondrial homeostasis by promoting the degradation of MARCHF5, an E3 ubiquitin ligase involved in mitochondrial quality control (30). CMA also regulates the turnover of enzymes involved in glucose and central carbon metabolism (3). Consistent with this, loss of hepatic CMA redirects metabolism toward increased glucose uptake while impairing glycogen synthesis (3). During fasting, CMA supports glucose homeostasis through the degradation of enzymes involved in glucose metabolism (31).

Collectively, these findings position CMA as a metabolic gatekeeper whose activity can critically shape tumor adaptation.

Tumor-suppressive functions of CMA

CMA contributes to cellular homeostasis by selectively degrading regulatory proteins that control proteostasis, metabolism, and cell-cycle progression (Figure 2). Through this selective proteolysis, CMA can exert tumor-suppressive functions by limiting the accumulation of oncogenic proteins, preserving genomic integrity, and maintaining proteostatic balance (13).

Figure 2.

Dual role of CMA in tumorigenesis: a balance between tumor suppression and promotion. CMA selectively degrades anti-oncogenic and pro-oncogenic substrates, thereby exerting context-dependent effects. CMA degrades anti-oncogenic substrates like CHK1, CSB and TTC28 (cell cycle/genome stability), HK-II, PKM2 and HIF1α (metabolic reprogramming), MDM2 (cell cycle/genome stability), CIP2A (cell cycle/proliferation), TCTP (proliferation/apoptosis), IL6ST and YAP1 (proliferation/metastasis) or oxidized proteins to limit tumor growth. CMA also modulates pro-oncogenic substrates such as RND3 (metastasis/proliferation), p73 (apoptosis/cell cycle), PED/PEA-15 and MST1 (apoptosis/cell cycle), BBC3/PUMA (apoptosis) and STAG2 (cell cycle) to promote tumor survival, progression, and stress adaptation. Created in BioRender. Madrigal Matute, J. (2026) https://BioRender.com/qz4a564

CMA inhibition increases transformation efficiency in oncogene-driven settings, suggesting that basal CMA can restrain malignant initiation in some contexts (22). In hepatocellular carcinoma (Table 1) reduced LAMP2A (CMA’s sole receptor) promotes proliferative and migratory phenotypes through accumulation of specific CMA substrates such as YAP1 and IL6ST (32). Recent work has also supported the tumor-suppressive role of CMA in hepatocellular carcinoma by demonstrating that LAMP2A deficiency promotes early malignant transformation through both hepatocyte-intrinsic and immune-dependent mechanisms which include STAG2 (Table 1, Figure 2) as a putative CMA substrate contributing to cell-cycle dysregulation and proliferation (33).

Table 1.

Selection of cancer-type specific CMA substrates. Molecular mechanisms and associated effects across different tumor types

Type of tumor	CMA’s role	Mechanism/substrates involved	Associated effect	Refs
Hepatocellular carcinoma	Tumor-suppressive	Reduced LAMP2A leads to accumulation of YAP1 and IL6ST; CMA deficiency promotes accumulation of STAG2 and impairs immune surveillance	Increased proliferation and migration, cell-cycle dysregulation, and promotion of hepatocarcinogenesis	(Desideri et al., 2023; (33)
Gastric cancer	Pro-tumoral	RND3 degradation	Increased proliferation	(58, 59)
Glioblastoma	Pro-tumoral	RND3 degradation and CMA activation in pericytes	Increased proliferation and T-cell immunosuppression	(58, 59)
Lung cancer	Pro-tumoral	Degradation of PED/PEA-15; shRNA-mediated LAMP2A knockdown	Enhanced tumor growth and metabolic fitness; CMA impairment reduces metabolic capacity	(63); (51)
Breast cancer	Pro-tumoral	shRNA-mediated LAMP2A knockdown modulates ATG5-dependent macroautophagy	Reduced tumor growth and metastasis upon CMA inhibition	(68)
Colorectal cancer	Pro-tumoral	Degradation of BBC3/PUMA	Reduced apoptosis and enhanced tumor cell survival	(64)

CMA also helps preserve genomic integrity by degrading selected proteins involved in the DNA damage response. For example, CSB (Cockayne syndrome group B) (Figure 2), a key factor in transcription-coupled repair, is a CMA substrate whose degradation enables the timely removal of CSB together with RNA polymerase II from repaired lesion sites, thereby preventing persistent repair complexes and maintaining genome stability (34). Similarly, CMA degrades the checkpoint kinase (CHK1) (Figure 2), facilitating the timely resolution of the DNA damage checkpoint and enabling cell-cycle reentry once repair has been completed (35). By promoting CHK1 turnover, CMA prevents its persistent nuclear accumulation and contributes to the stabilization of the MRN complex (Mre11–Rad50–Nbs1), which is essential for proper DNA repair (36). In the absence of CMA, nuclear levels of phosphorylated CHK1 increase, leading to disruption of DNA damage response and impaired genome maintenance (36). TTC28 has also been identified as a CMA substrate required for genome stability during mitosis or cytokinesis. By regulating TTC28 turnover, CMA helps ensure proper mitotic progression, whereas TTC28 accumulation (Figure 2), frequently observed in numerous cancers, has been associated with chromosomal instability (37).

CMA participates in cell cycle control by regulating the CIP2A–PP2A–MYC axis, which is frequently altered in cancer (38). CIP2A inhibits the phosphatase PP2A, thus preventing dephosphorylation of MYC at Ser62 and tumor suppression (38). Phosphorylated MYC cannot be efficiently recognized by ubiquitin ligases or targeted for proteasomal degradation sustaining tumor growth (39). By promoting CMA-mediated degradation of CIP2A (Figure 2), PP2A activity is restored, leading to MYC dephosphorylation and tumor suppression (22).

MDM2 levels are elevated in multiple cancer types (40), and it has been identified as a CMA substrate in specific cellular contexts (41). MDM2 is the main E3 ubiquitin ligase of the tumor suppressor p53 and has also been implicated in tumor neovascularization and dissemination (40). In cells treated with the polyphenol hispolon, MDM2 degradation is attenuated upon LAMP2A silencing, supporting the idea that CMA contributes to the regulation of MDM2 turnover (41). Together, these findings suggest that CMA-mediated turnover of MDM2 may contribute to the regulation of p53-dependent tumor suppressive pathways (Figure 2).

TCTP is an anti-apoptotic protein implicated in DNA damage repair and mitotic progression through stabilization of the mitotic spindle (42). TCTP is frequently overexpressed in many cancer types, and its overexpression is associated with poor prognosis due to its anti-apoptotic activity (43, 44). Notably, TCTP has been identified as a CMA substrate (23), highlighting the role of CMA-mediated degradation in restraining its intracellular abundance and limiting its pro-survival and pro-tumorigenic effects (Figure 2).

Various conditions associated with oxidative stress, including obesity, high-fat diets, metabolic disorders, and environmental pollution, promote the accumulation of oxidized proteins and may ultimately compromise CMA activity (45, 46). In this context, CMA acts as a cellular defense mechanism with anti-oncogenic potential by promoting the selective degradation of oxidized and pro-oncogenic proteins (13). Mechanistically, moderate oxidative stress activates CMA, as reactive oxygen species (ROS) increase de novo synthesis of LAMP2A (47). In parallel, ROS activates NRF2 signaling, a master regulator of antioxidant responses, whose activity is further modulated by CMA through the degradation of its inhibitor KEAP1 (48, 49). Additionally, in T lymphocytes, oxidative stress induces NFAT1-dependent LAMP2A transcription, reinforcing CMA activation and facilitating the degradation of negative regulators of immune activation (50). Together, these observations highlight the role of CMA as a protective mechanism that limits oxidative and proteotoxic stress contributing to tumor-suppressive cellular programs.

CMA as a regulator of tumor progression and maintenance

In contrast to its tumor-suppressive functions, CMA can be exploited by tumor cells to support growth and proliferation (51). CMA contributes to tumor progression by selectively degrading proteins involved in growth control, cell-cycle arrest, immune surveillance, as well as tumor suppressors and regulators of apoptosis (Figure 2) (52). In addition, CMA can promote tumor fitness by facilitating metabolic reprogramming, as mechanistic studies indicate that this pathway sustains the metabolic flexibility required for the maintenance and growth of established tumors (53, 54). Consistent with this, clinical and translational studies across multiple cancers have associated higher expression of CMA markers (e.g., LAMP2A) with worse outcomes. These findings suggest that, at least in subsets of patients, a “high-LAMP2A signature” may reflect tumor dependency (55, 56).

The protein Rho family GTPase 3 (RND3) regulates the actin cytoskeleton controlling processes such as mitosis and cell migration (57). In gastric cancer and glioblastoma, RND3 has been identified as a CMA substrate (Figure 2). Reduced RND3 levels are associated with increased tumor cell proliferation (Table 1) (58, 59), suggesting that excessive CMA activity may be exploited by tumor cells to support proliferation. CMA also regulates HIF1α levels through its selective degradation (Figure 2). Because HIF1α can act as a negative regulator of DNA replication and induce cell-cycle arrest, its lysosomal turnover facilitates cell-cycle progression and proliferation under certain contexts (60). Similarly, CMA-mediated degradation of the tumor suppressor P73 has been linked to enhanced proliferative capacity (Figure 2) (61). CMA-mediated degradation of the tumor suppressor MST1 decreases the levels of downstream pro-apoptotic and anti-growth signaling, thereby promoting tumor progression (62). Similarly, PED/PEA-15 acts as a tumor suppressor in lung cancer when dephosphorylated, but increased CMA activity leads to recognition and degradation of this non-phosphorylated form (Table 1, Figure 2) (63). Likewise, degradation of pro-apoptotic proteins can contribute to therapeutic resistance. This is exemplified by BBC3/PUMA, whose CMA-mediated degradation reduces apoptosis in drug-treated cancer cells (Table 1, Figure 2) (64).

Upon genotoxic stress, CMA is activated and contributes to tumor cell adaptation (13). Consistently, LAMP2A knockdown or knockout enhances sensitivity to DNA-damaging agents such as cisplatin or methyl methanesulfonate (MMS) and is associated with increased γH2AX levels, an early indicator of double-strand breaks and replicative stress (29, 65).

In glioblastoma, tumor cells can induce upregulation of CMA in pericytes, necessary to maintain an anti-inflammatory phenotype that inactivates T cells for tumor progression (Table 1) (66). In lung cancer, cells with CMA impairment induced by shRNA targeting LAMP2A exhibit a marked reduction in their metabolic capacity, as shown in ECAR assays, pointing to metabolic inflexibility (Table 1) (51).

Furthermore, CMA targets key metabolic enzymes such as pyruvate kinase isozyme type M2 (PKM2) and hexokinase 2 (HK2) (Figure 2). Decreased degradation of these enzymes, whether due to mutation or post-translational modification, enhances glycolytic flux and sustains the metabolic reprogramming characteristic of the Warburg metabolic phenotype (31, 67). In addition, in vivo studies have shown that CMA-deficient cells have a reduced capacity to form tumors and show a decreased metastatic capacity and reduced size of preexisting tumors (51). Also, LAMP2A knockdown inhibits breast cancer growth and metastasis in vivo partly through downregulation of ATG5-dependent macroautophagy (Table 1) (68), suggesting that the combined loss of two key proteostatic pathways such as CMA and macroautophagy contributes to tumor progression and metabolic adaptation.

Altogether, these findings position CMA as a context-dependent regulator of tumor progression, whose activity may represent both a metabolic advantage for cancer cells and a potential therapeutic vulnerability. The net impact of CMA on cancer progression is dictated by the balance between its pro-survival metabolic rewiring and the preservation of cellular integrity.

3. Diet, CMA and cancer: a mechanistic interface

Lifestyle adjustments have long been recognized as a key point of disease prevention, with evidence demonstrating that defined dietary regimens, exercise, sleep optimization and stress control can profoundly influence metabolic health and disease risk (69, 70). Nutritional interventions and deliberately designed strategies to modify metabolic status at the individual or population level, have shown benefits in obesity, metabolic syndrome, and associated comorbidities, including cancer (71). Experimental and clinical studies consistently demonstrate that nutrient availability is one of the most robust physiological regulators of autophagy, highlighting the intimate link between diet and intracellular quality control mechanisms (72). At the same time, dietary patterns are known to influence cancer incidence and progression. Although the mechanistic bases underlying these associations remain incompletely defined, autophagy has emerged as a potential mechanistic mediator linking nutrient availability to tumor biology (71, 72). The widespread perception that diet can meaningfully alter cancer outcomes is reflected by patient behavior, as nearly half of individuals diagnosed with cancer report changing their dietary habits in an attempt to improve treatment efficiency and survival (73).

Despite this strong interest, the scientific foundation supporting many dietary recommendations in oncology remains uneven. Much of the guidance provided by national cancer organizations, including the National Cancer Institute (NCI), and the European Society for Clinical Nutrition and Metabolism (ESPEN), focuses on preventing malnutrition, maintaining caloric intake, and mitigating treatment-associated metabolic alterations (74). These recommendations largely mirror guidelines for the general population, emphasizing fresh fruits, vegetables, whole grains, and adequate protein while limiting processed foods, refined sugars, and excess fat. However, these strategies are not primarily designed to exploit tumor-specific metabolic vulnerabilities. At the same time, professional and public debates regarding optimal macronutrient composition as low-fat versus high-fat/low-carbohydrate diets, the role of processed carbohydrates, and the balance between protein sources have been open for years (75). The heterogeneity of dietary approaches and inconsistent mechanistic grounding have complicated efforts to define evidence-based nutritional interventions for cancer therapy. Therefore, a deeper understanding of cancer metabolism will provide a more rational framework for evaluating dietary modulation in oncology.

Tumor metabolism is not uniform but instead shaped by tissue of origin, microenvironmental peculiarities, systemic host metabolism, specific oncogenic mutations, tumor suppressor loss or epigenetic remodeling (76). Metabolic adaptation supports every stage of tumor progression, generally enabling increased nutrient uptake, enhanced biosynthesis, redox homeostasis, and survival under stress (76). Moreover, tumor cells actively remodel their microenvironment, taking over stromal and immune cells to secure nutrient support and buffer metabolic stress affecting the surrounding tissue balance (77). The nutrient composition accessible to tumors often differs substantially from that of adjacent normal tissue, further complicating extrapolation from systemic dietary intake to tumor-intrinsic metabolism (78).

Autophagy represents a central node in this integration. Nutrient deprivation robustly activates autophagic pathways, allowing cells to recycle intracellular components and maintain energy homeostasis (7). While macroautophagy has been extensively studied in cancer biology, CMA has emerged as a highly selective lysosomal degradation pathway with distinct regulatory and functional properties. Through this selectivity, CMA fine-tunes the abundance of specific metabolic enzymes, transcription factors, and stress response mediators (7). CMA activity is tightly controlled by nutrient status through lysosomal signaling networks that sense energy availability and growth factor cues. Under nutrient-rich conditions, CMA is restrained, whereas fasting or metabolic stress enhances lysosomal receptor dynamics and substrate flux, allowing adaptive proteome remodeling (7). Thus, CMA functions as a molecular interface between extracellular nutrient availability and intracellular metabolic configuration. In the context of cancer, this regulatory axis becomes particularly relevant. Tumor cells frequently operate under fluctuating nutrient and oxygen conditions, and CMA can support adaptation by removing damaged proteins, maintaining redox balance, and selectively degrading metabolic regulators (13). Conversely, in certain contexts, CMA contributes to tumor suppression by preserving proteostasis and limiting proteotoxic stress (13).

Diet-driven modulation of CMA therefore represents a mechanistically supported approach to understand how nutritional interventions might influence tumor biology. Alterations in caloric intake, macronutrient balance, or specific amino acid availability could reshape tumor proteostasis by adjusting CMA activity, and so impacting metabolic enzyme stability, signaling cascades, and stress resilience (79). Moreover, the effects of nutritional modulation on CMA are unlikely to be restricted to tumor cells alone. Stromal, immune, and other cell populations within the tumor microenvironment may exhibit distinct CMA responses, further influencing therapeutic outcomes. The systemic metabolic state of the host, particularly in metabolic diseases, and aging, conditions characterized by altered autophagic activity, adds an extra layer of complexity (80).

Additionally, pharmacological treatments, while targeting metabolic dependencies of the tumor, create selective liabilities, generating tumors with adaptive resilience in some cases (81). Understanding how these systemic interventions translate into tumor-specific effects requires integrating metabolism with intracellular proteostasis pathways that govern adaptive responses to nutrient stress. Future studies should directly test whether defined nutritional interventions, such as fasting, CR, lipid-enriched diets, or specific amino acid modulation, alter CMA flux in tumor and non-tumor tissues, and whether these changes modify proteome turnover, immune function, treatment tolerance, or therapeutic response. This is a complex field in which tumor genotype, tissue of origin, and nutrient availability shape proteostasis and CMA activity, influencing how nutritional interventions can be strategically combined with chemotherapy, targeted therapies, or immunotherapy.

4. Nutritional modulation of CMA: molecular and physiological mechanisms

CMA is uniquely sensitive to the nutritional and metabolic state of the cell (7, 45). This pathway responds to both short- and long-term dietary cues through finely tuned regulatory mechanisms that work at the levels of lysosomal composition (16, 82), and intracellular signaling (17, 83). This sensitivity places CMA at the intersection of nutrition, metabolism, and cellular stress responses (84), making it particularly relevant for understanding how dietary interventions may influence cancer risk and therapeutic outcomes. Here, we review some of the molecular and physiological mechanisms through which nutrition modulates CMA, focusing on nutrient-specific effects, upstream signaling pathways, and recent experimental evidence from cellular and animal models.

Nutritional interventions and their effects on CMA activity

Fasting and CR are the best-characterized nutritional interventions known to modulate CMA (7, 84). Both paradigms support a coordinated metabolic response aimed at preserving cellular viability under conditions of limited nutrient availability. CMA activation during nutrient deficiency is not only a passive consequence of metabolic stress but rather a tightly regulated adaptive process (7, 84).

Beyond physiological studies, the translational relevance of CMA modulation has been explored using caloric restriction mimetics (CRMs), pharmacological agents that recapitulate key biochemical and functional features of CR without reducing caloric intake (79). Acute administration of CRMs to aged mice has been shown to robustly activate CMA across multiple tissues, and this activation is required for the enhanced resistance to lipid dietary challenges conferred by CRM treatment (79). These findings identify CMA as a critical effector of CR-associated metabolic resilience and suggest that pharmacological CMA activation may capture some of the protective benefits of dietary interventions.

Under nutrient deprivation, cells with blocked CMA increase macroautophagy activity as a compensatory mechanism (4).. Importantly, although both macroautophagy and CMA are activated during nutrient deprivation, their temporal dynamics and functional contributions differ. Macroautophagy is rapidly induced during the early phases of starvation and primarily supports bulk degradation of cytoplasmic components and organelles to sustain energy production. While CMA activation is typically delayed and becomes more prominent during prolonged nutrient limitation, where it selectively degrades individual proteins involved in metabolic regulation, stress adaptation, and proteostasis (85). This temporal and substrate specificity suggests that CMA contributes to the fine-tuning of the cellular response to nutritional stress rather than simply duplicating the functions of macroautophagy. Moreover, the two pathways are functionally interconnected, as inhibition of CMA can trigger compensatory macroautophagy activation, whereas prolonged CMA deficiency ultimately compromises the capacity of other proteolytic systems to maintain cellular homeostasis (85). In this line, in aged mice with CMA deficiency in the liver, the compensatory capacity of macroautophagy and the proteasomal system is lost, leading to liver dysfunction, alterations in proteostasis, and accelerated metabolic dysregulation (21). Therefore, the beneficial effects of fasting and caloric restriction are likely mediated by coordinated but non-redundant contributions of both autophagic pathways.

Intermittent fasting (IF), which alternates periods of feeding and fasting without an overall reduction in caloric intake, has gained increasing attention due to its broad metabolic and health benefits (72). IF introduces cyclical activation and repression of nutrient-responsive pathways, including autophagic processes, and profoundly affects adipose tissue function, insulin sensitivity, and systemic glucose homeostasis. These oscillatory metabolic states promote evolutionarily conserved adaptive responses involving stress resistance and autophagy (86). IF also reshapes circadian rhythms of metabolic hormones such as insulin and leptin, whose levels fluctuate in response to nutrient availability (87). At the tissue level, IF induces metabolic remodeling characterized by reduced hepatic lipid accumulation, reprogramming of adipose tissue, attenuation of obesity-associated dysfunction, and increased lean mass (88, 89).

While the direct effects of IF on CMA activity remain incompletely defined, repeated fasting cycles may train the CMA machinery, enhancing its inducibility and preserving CMA function over time. The adaptive reinforcement of CMA may contribute to improved proteostasis and metabolic resilience during aging and in age-associated diseases, including cancer, although this hypothesis awaits direct experimental validation.

Macronutrient composition further refines CMA regulation, particularly in the context of dietary lipid overload. Lipid-enriched diets engage nutrient- and stress-sensing pathways that converge on lysosomal degradative systems and can impair CMA activity. In experimental models, this has been shown using high-fat diets containing 60% kcal from fat, largely derived from lard, cholesterol-enriched diets containing 2% cholesterol, and Western-type diets enriched in saturated fat, cholesterol, and cholic acid (3, 16, 90). Sustained dietary lipid overload, including high-fat or high-cholesterol diets, decreases CMA activity due to impaired LAMP2A stability and altered lysosomal membrane dynamics, representing a mechanistic link between lipid excess, defective proteostasis, and increased cardiometabolic and cancer risk (3, 16, 24, 90).

Finally, emerging evidence suggests that ketone bodies can directly influence CMA. An early in vitro study demonstrated that ketone bodies stimulate CMA activity in human fibroblasts (91). Despite this observation, systematic analyses of CMA regulation in response to ketogenic diets in vivo remain scarce. Beyond their direct effects, ketogenic diets generate a low-glucose, high-ketone metabolic environment characterized by reduced insulin signaling and increased oxidative pressure in tumor cells (92), factors that may indirectly shape CMA dynamics. Given the growing interest in ketogenic interventions in cancer and metabolic disease, defining how ketone-driven metabolic states intersect with CMA regulation represents an important area for future investigation.

These findings underscore the importance of considering not only caloric intake but also macronutrient quality in the physiological and pathological regulation of CMA.

Signaling pathways in CMA modulation and the role of specific nutrients

At a mechanistic level, CMA regulation is highly dynamic and varies across physiological and pathophysiological contexts. Nutrient availability modulates CMA through signaling pathways that sense cellular energy status and growth factor input, thereby coupling lysosomal proteostasis to metabolic state. Among these pathways, mechanistic target of rapamycin (mTOR) signaling has emerged as a central regulatory node. While mTORC1 activation is classically associated with suppression of macroautophagy under nutrient-rich conditions (93), CMA is regulated through a distinct branch involving mTORC2 and its downstream effector AKT1 (83). In nutrient-replete states, mTORC2-dependent phosphorylation of AKT1 maintains inhibitory phosphorylation events at the lysosomal membrane that restrain CMA activity. During fasting or nutrient deprivation, this inhibitory axis is actively dismantled. The phosphatase PHLPP is recruited to the lysosomal membrane, where it dephosphorylates and inactivates AKT1, thereby relieving repression and enabling CMA activation (83). This lysosome-centered signaling module highlights a key conceptual distinction between CMA and macroautophagy and underscores the importance of localized signaling events in fine-tuning CMA flux.

The signaling pathways governing CMA can diverge substantially between physiological and pathological states. This distinction is particularly relevant in cancer, where oncogenic signaling frequently sustains AKT activity even under conditions of nutrient limitation, effectively uncoupling CMA regulation from normal dietary cues (13, 94). In such settings, persistent activation of growth factor–dependent pathways may override nutrient-sensing mechanisms, reshaping CMA regulation to favor tumor cell survival.

At the lysosomal level, nutritional modulation of CMA is largely mediated through post-transcriptional regulation of LAMP2A, the rate-limiting CMA receptor. Prolonged CR enhances CMA activity primarily by increasing the stability of LAMP2A at the lysosomal membrane, rather than by markedly elevating its transcription (79). In parallel, changes in lysosomal lipid microdomains play a critical role in CMA regulation, as membrane composition directly influences LAMP2A multimerization and the efficiency of substrate translocation into the lysosomal lumen (15). Together, these mechanisms increase the stability and multimerization of LAMP2A at the lysosomal membrane, promoting the formation of functional CMA translocation complexes during sustained nutrient stress.

Beyond caloric availability per se, individual nutrients exert distinct effects on CMA through dedicated, though still incompletely defined, signaling pathways. Alterations in dietary lipid composition can deeply affect lysosomal membrane properties modulating LAMP2A dynamics and CMA activity (16, 95). Diets enriched in saturated fatty acids have been associated with impaired lysosomal function and reduced CMA efficiency, whereas unsaturated fatty acids appear to preserve membrane fluidity and support CMA activity (16). In addition, lipid-derived signaling molecules can influence oxidative stress and inflammatory tone, indirectly shaping chaperone function and CMA substrate availability (24, 96).

CMA also responds selectively to amino acid availability, with certain essential amino acids activating nutrient-sensing pathways that suppress autophagic processes. For example, D-cysteine activates CMA in cerebellar Purkinje cells through hydrogen sulfide production and NRF2 activation (97), illustrating that amino acids can influence CMA via redox- and stress-responsive pathways. More broadly, amino acid sufficiency signals through nutrient sensors to regulate the availability and stability of the CMA-related components, modulating CMA activity (1).

Glucose metabolism and redox signaling further intersect with CMA regulation. Hyperglycemic stress activates CMA through an NFE2L2 (NRF2)-dependent pathway, conferring cytoprotective effects that are largely mediated by LAMP2A (98). These findings suggest that glucose availability may shape CMA-dependent cytoprotection under metabolic stress. In cancer, this raises the hypothesis that interventions that reduce glucose availability could attenuate CMA-mediated adaptive responses in tumor cells, potentially limiting proteostatic and redox buffering capacity during therapy.

Micronutrients, particularly dietary polyphenols, have been widely implicated in autophagy regulation (99), although direct evidence linking these compounds to CMA remains limited. Among antioxidant micronutrients, vitamin E has been reported to reduce LAMP2A levels under conditions of oxidative stress, suggesting that redox balance may indirectly influence CMA receptor stability (100). However, the extent to which individual micronutrients exert direct and selective effects on CMA activity remains to be fully elucidated.

Collectively, nutrient-specific effects on CMA converge on shared energy- and stress-signaling pathways, highlighting the integrative nature of CMA regulation. This convergence helps explain why dietary interventions may exert synergistic or antagonistic effects on CMA activity. Dissecting how these strategies differentially affect CMA in healthy versus malignant cells will be essential for translating these insights into effective prevention and therapy.

5. Controversies and challenges in the field

A major limitation in the CMA-nutrition-cancer field is the lack of robust clinical trials that include CMA endpoints. While multiple studies have explored short-term fasting, fasting-mimicking diets (FMD), or fasting-supportive regimens around cancer therapy, they typically report feasibility, safety, metabolic changes, and selected clinical outcomes (101–103). However, these studies do not evaluate CMA activity in patients, leaving the mechanistic attribution to CMA largely inferential.

On the preclinical side, interpretation is frequently complicated by marked experimental heterogeneity: CMA responses can vary by (i) tissue (liver vs adipose vs immune compartments) (3, 50, 104), (ii) cell state and differentiation (e.g., adipocytes vs adipocyte precursors) (95), (iii) host context (age, obesity/metabolic status) (95), and (iv) the nutritional stimulus itself (fasting duration, CR vs IF vs macronutrient composition) (105, 106).

The utmost persistent challenge is methodological: measuring CMA in humans. The most widely accepted approaches to quantify CMA activity in experimental systems rely on the KFERQ reporter, lysosomal isolation and assays of substrate binding/uptake/degradation (approaches that capture a flux-like readout), which are not readily compatible with repeated sampling in clinical nutritional studies (107). Consequently, many human studies default to static proxies (e.g., LAMP2A levels by IHC or immunoblot), which can be informative for stratification but are imperfect surrogates for dynamic CMA flux (107). Mechanistically, this limitation is non-trivial: LAMP2A function depends on membrane organization and dynamic complex assembly, and not only on total abundance, which can decouple expression from functional CMA capacity (15, 17).

Finally, an often-underappreciated issue in nutritional intervention studies is timing. CMA activation during starvation has been described as a later-phase adaptive program (relative to early macroautophagy activation), meaning that two interventions both labeled as “fasting” may engage different autophagy programs depending on their duration and sampling window (7). This temporal complexity contributes to inconsistent findings across models and complicates translation.

Ongoing debates: optimal nutrition, clinical context, and CMA modulation strategy

A central conceptual controversy is whether nutritional interventions that tend to promote autophagy-related programs would be beneficial or detrimental when CMA itself can be pro- or anti-tumorigenic depending on context (13). These observations drive an unresolved debate regarding CMA activation or inhibition: should interventions aim to restore CMA in normal/aging tissues while avoiding enhancing CMA within tumors, or can diet be used to selectively modulate CMA in a beneficial compartment-specific manner?

A second debate concerns the optimal nutritional strategy and the clinical setting in which it is tested. Short-term fasting or FMD regimens are often viewed as more feasible than chronic CR in oncology, particularly in patients at risk of weight loss or cachexia; however, feasibility remains variable and adherence is a recurring limitation (72). Meanwhile, ketogenic or fasting-supportive diets may modulate CMA-relevant biology via ketone bodies (91), but they can also entail high-fat exposure that may differentially impair CMA in certain tissues (16), creating mechanistic ambiguity that cannot be resolved without direct CMA readouts.

A third debate is patient stratification: nutritional interventions are frequently tested broadly, yet CMA biology suggests thattumor CMA status may critically determine benefit vs harm. This argues for future trials to consider CMA-informed enrichment strategies, even if initially through imperfect proxies (LAMP2A IHC) alongside metabolic and immune profiling (55, 56, 108).

Finally, cancer-associated cachexia represents an additional translational constraint for nutrition-based CMA strategies. While the present review focuses primarily on therapeutic/metabolic nutrition approaches aimed at modulating tumor-host biology and treatment response, established cachexia often requires supportive nutritional care to preserve body weight, muscle mass, function, and quality of life (109). Moreover, direct evidence linking CMA to cancer cachexia remains limited, whereas broader autophagy pathways, particularly macroautophagy, have been implicated in cancer-induced muscle wasting (110). Therefore, CMA-oriented nutritional interventions may require careful adaptation in cachectic patients, where systemic inflammation, anorexia, muscle catabolism, and impaired anabolic responsiveness can compromise both feasibility and mechanistic interpretation.

6. Future perspectives and research directions

From a nutritional oncology perspective, CMA is particularly compelling because (i) it is modulated by nutrient availability and dietary composition in metabolically central organs, and (ii) it can be rewired in tumors in ways that support metabolic fitness, therapy resistance, and immune evasion or, conversely, restrain malignant traits depending on tumor state and lineage (7).

Research priorities

Progress in nutritional oncology will require standardized approaches to measure CMA flux, identify tumors or tissues with CMA dependency, and determine whether nutritional interventions can reproducibly modulate this pathway in clinically relevant settings. Several priorities stand out.

1. A key unmet need is the validation of CMA biomarker panels capable of detecting diet-induced changes in CMA activity and distinguishing pathway activation from changes in LAMP2A abundance alone (111–113). Future studies should combine feasible clinical readouts, such as tissue IHC or blood transcript signatures, with experimentally validated measures of CMA flux in preclinical or ex vivo systems (15). Beyond total LAMP2A levels, biomarker strategies should incorporate LAMP2A localization, complex assembly, and state-specific post-translational modifications. In this regard, evidence that LAMP2A phosphorylation regulates CMA activity supports the potential use of phospho-LAMP2A and related functional-state markers as measurable indicators of CMA activation (114).

2. Substrate-informed biomarkers: from KFERQ motif discovery to targeted panels. A major barrier to CMA biomarker development is that CMA substrates are numerous and context specific. Two complementary approaches can help identify candidate CMA substrates relevant to nutrition-cancer interactions. First, proteome-scale computational analyses have systematically screened proteins for KFERQ-like motifs and generated tools, including a public KFERQ motif finder, that enable the identification of candidate substrates and motif types, including canonical and post-translationally generated motifs (115). In parallel, multiplex quantitative proteomics of isolated CMA-active lysosomes (“targetome” analysis) has identified CMA-regulated pathways beyond classical metabolism, including components of the translation initiation machinery (116, 117).

3. Transcriptomic CMA signatures and “CMA activation scores”. Recent studies have proposed and validated a CMA activation score based on the expression of known CMA effectors and modulators, emphasizing its practicality when flux measurement is difficult (90), and supporting the premise that transcriptomic/omic correlates of CMA should be validated against in vivo CMA flux measurements (79).

   Beyond biomarker development, several broader translational priorities emerge regarding tumor heterogeneity, clinical implementation, and patient stratification.

4. Characterize CMA responses across tumor types, tumor cell states, and microenvironments. Cancer data increasingly indicate that CMA activity and dependency are not uniform across tumors, but are shaped by tumor lineage, stemness, epithelial–mesenchymal state, or microenvironmental pressures (13, 118). These findings highlight the need to build tumor-type and tumor-state atlases of CMA that distinguish: CMA-high, CMA-dependent tumors that may be vulnerable to CMA suppression; CMA-deficient contexts where CMA restoration could restrain metastatic programs; and mixed tumors where CMA differs across subclones or niches.

5. Integrate CMA endpoints into nutritional oncology trials using translationally feasible sampling. The absence of CMA endpoints in most dietary oncology trials represents a translational gap. Future studies should incorporate serial peripheral readouts, baseline tumor profiling, and ex vivo validation of CMA flux to evaluate whether CMA modulation serves as a pharmacodynamic endpoint of nutritional interventions or as a predictive biomarker of treatment response.

6. Although this review focuses primarily on adult and age-related cancers, pediatric oncology represents an important unmet area for CMA research. Direct evidence linking CMA regulation to pediatric tumors remains scarce (119), and nutrition-focused studies in pediatric oncology are still limited and largely centered on nutritional status, body composition, supplementation, or supportive care rather than mechanistic endpoints (120). Given the age-dependent regulation of CMA and the critical role of nutrition during development and cancer therapy, future studies should determine whether CMA contributes to tumor biology, treatment tolerance, or nutritional vulnerability in pediatric cancer patients.

Technological advances shaping the next phase of CMA research in nutritional oncology

A decisive methodological breakthrough for CMA has been the development of photoconvertible/photoactivatable fluorescent reporters that switch from diffuse cytosolic localization to punctate lysosomal localization upon CMA activation. The 2011 photoconvertible reporter work enabled CMA monitoring in living cells, highlighted cell-type dependence of basal and inducible CMA and demonstrated compatibility with high-content microscopy (111). Building on this, a 2020 transgenic reporter mouse enabled dynamic in vivo imaging of CMA activity across organs and under stress, revealing spatial and temporal heterogeneity at single-cell resolution and supporting multiorgan assessment of pharmacological modulators (112). These reporter platforms are highly relevant to nutritional oncology because dietary interventions often generate heterogeneous, tissue-specific metabolic states. Reporter mice provide a way to quantify how the same nutritional regimen may differentially modulate CMA in liver, immune lineages, or tumor-bearing tissues.

Furthermore, genetically engineered models can help to demonstrate causal attribution of CMA to diet–tumor phenotypes. On the tumor side, models that directly manipulate CMA components in cancer cells are now being deployed to dissect tumor-state contingencies (e.g., epithelial vs mesenchymal dependence) (52). An additional emerging direction is the integration of reporter models with single-cell transcriptomic data to define which tissues, and cell types show the strongest CMA changes with age and sex, two variables that strongly impact both cancer incidence and nutritional tolerance in patients (106).

Finally, chemical probes can be used as “measurement accelerators” and tool compounds for biomarker validation. Selective pharmacological modulation of CMA is increasingly feasible and can be exploited as a methodological asset. For example, CMA activation through retinoic acid receptor alpha (RARα) regulation has been mechanistically clarified, providing a framework for selective CMA activation in vivo (94). Similarly, inhibition of class I PI3K or PDPK1 was shown to activate CMA, offering repurposable compounds as perturbation tools (121).

To date, most efforts to pharmacologically modulate CMA have been focused on aging and age-associated disorders where CMA activation appears beneficial. However, in the context of cancer, where CMA could sustain tumor growth and metabolic adaptation, its inhibition may also represent a more effective therapeutic strategy, underscoring the need to expand current research toward the development of selective CMA inhibitors.

Altogether, these advances position CMA-targeting chemical probes as a promising entry point for context-specific therapeutic interventions that exploit the dual nature of CMA in human disease.

Long-term vision: CMA-guided personalized nutritional interventions in oncology

A plausible long-term trajectory is precision nutritional oncology guided by CMA profiling, where dietary interventions are tailored not only to tumor genotype but also to tumor CMA state and host CMA capacity. The proposed long-term model is therefore: (i) stratify patients by tumor CMA phenotype (and key host factors such as baseline metabolic status), (ii) select nutritional regimens likely to be beneficial for that CMA/tumor context, and (iii) monitor CMA-linked biomarkers longitudinally to adapt timing and intensity.

In this long-term vision, personalized nutrition would be developed as a mechanism-guided co-therapy integrated with tumor biology, systemic metabolism, and immune context. CMA provides a biologically plausible interface for this approach by linking nutrient availability to selective proteome remodeling, metabolic adaptation, and stress responses. Future studies should define how specific dietary inputs modulate CMA across tissues, tumor states, and treatment contexts, and whether these changes enhance therapeutic efficacy or reinforce tumor resilience. Importantly, the efficacy of CMA-based nutritional or therapeutic strategies will ultimately depend on lysosomal competence, including membrane integrity, LAMP2A dynamics, substrate translocation, and proteolytic capacity; thus, lysosomes should be viewed as active determinants of the biological consequences of CMA modulation.