Autophagy in Cancer Progression and Therapeutics

The paper addresses the complex and context-dependent role of autophagy in cancer, highlighting its dual functions in both tumor suppression (via clearance of damaged components) and tumor promotion (by supporting biosynthetic needs and therapy resistance). The purpose is to summarize recent advances that clarify when and how autophagy should be modulated during cancer therapy. The importance of timing, drug concentration, and cancer type/stage in determining whether autophagy supports survival or induces cell death is emphasized, with the overarching aim of informing therapeutic strategies that harness or inhibit autophagy appropriately.

- Chemotherapy induces multiple cellular stress responses, including autophagy, apoptosis, and senescence [5]. Doxorubicin (DOX), while effective, is limited by cardiotoxicity linked to mitochondrial reactive oxygen species [6]. Deficiency of LAMP-2 impairs autolysosome formation and causes accumulation of autophagic vacuoles and cardiomyopathy, underscoring the necessity of balanced autophagy for cardiac health [7,8]. Excessive autophagy can also result in cardiac dysfunction [9]. Maintaining basal autophagy in DOX-treated rats prevents mitochondrial oxidative damage, whereas reducing autophagosome formation below baseline disrupts cardiac redox balance [10]. - In chronic myelogenous leukemia, pyrimethamine (Pyri) activates autophagy in a time- and concentration-dependent manner and increases apoptosis in a concentration-dependent but time-independent manner, potentially through suppression of STAT5, thereby modulating different forms of cell death [11]. - In glioblastoma, the therapeutic paradigm has shifted from whether to modulate autophagy to when to modulate it. While autophagy can facilitate chemoresistance, its overactivation may synergize with apoptosis to induce cell death, suggesting the need to tailor interventions based on autophagy flux levels [12]. - In acute myeloid leukemia (AML), AraC-resistant cell lines do not exhibit elevated autophagy activity, and autophagy inhibition does not re-sensitize them to cytarabine; in contrast, AraC-sensitive cells increase autophagy during treatment, and autophagy inhibition can enhance AraC cytotoxicity, though without additive cytotoxic effects beyond individual treatments [13]. - Adenoviruses can induce autophagy to support virus replication and oncolysis, with implications for oncolytic virotherapy [1,2].

- Autophagy has a dual role in cancer: it can either promote tumor growth by fulfilling biosynthetic demands and mediating drug resistance or suppress tumorigenesis by removing damaged organelles and dysfunctional cells. - Cardiac autophagy must be finely balanced: LAMP-2 deficiency leads to cardiomyopathy via impaired autophagosome–lysosome fusion, while overexpression of autophagy can also cause cardiac dysfunction. In DOX models, maintaining basal autophagy protects mitochondria from oxidative damage; autophagy suppression below baseline disrupts cardiac redox homeostasis. - Timing and dose matter: In CML cells, Pyri induces autophagy (time- and concentration-dependent) and apoptosis (concentration-dependent), likely via STAT5 suppression, indicating the potential to regulate distinct cell death pathways by adjusting exposure parameters. - In glioblastoma, therapeutic benefit may depend on when autophagy is modulated; overexpression can switch from cytoprotective to cytotoxic, synergizing with apoptosis. - In AML, autophagy’s contribution to AraC resistance is context-specific: resistant cells do not show increased autophagy and are not re-sensitized by autophagy inhibition, whereas sensitive cells exhibit increased autophagy during treatment and can be made more susceptible by autophagy inhibition, albeit without additive cytotoxicity. - Figure concept: Chemotherapy elevates autophagy from basal flux to high flux; depending on tumor type and stage, basal autophagy often confers drug resistance, while time-dependent high autophagy overexpression at higher drug concentrations more often leads to cell death and tumor suppression, emphasizing the need to control drug concentration and exposure time.

The compiled evidence underscores that autophagy’s effects on cancer therapy outcomes are highly context-dependent. Maintaining or inhibiting autophagy can either protect normal tissues (e.g., heart during DOX therapy) or enhance tumor cell killing, depending on timing, magnitude of autophagy flux, and cancer type/stage. In glioblastoma and CML models, strategic modulation of autophagy (including overactivation at specific times/doses) may potentiate apoptosis and improve therapeutic efficacy. Conversely, in AML, autophagy inhibition does not universally overcome drug resistance, highlighting that resistance mechanisms may be autophagy-independent in certain contexts. These findings suggest therapeutic strategies should pivot from a binary approach (induce vs inhibit) to a dynamic one that monitors and targets autophagy flux over time, tailored to tumor biology and treatment schedules.

Autophagy is integral to cellular homeostasis and plays a dual role in cancer biology, contributing to both tumor suppression and progression. The Special Issue highlights that therapeutic outcomes depend on the timing and degree of autophagy modulation, drug concentration, and cancer context. Key contributions include evidence that maintaining basal autophagy can protect against DOX-induced cardiotoxicity, that targeted modulation (including potential overactivation) can synergize with apoptosis in glioblastoma and CML, and that not all drug resistance (e.g., in AML) is reversible by autophagy inhibition. Future research should focus on real-time assessment of autophagy flux in patients, development of biomarkers to guide when and how to modulate autophagy, and designing time- and dose-dependent protocols that account for tissue-specific and tumor-specific responses.

- The role of autophagy in therapy remains unclear in many contexts, with outcomes varying by tumor type, stage, and treatment schedule; thus, generalizability is limited. - Elevated basal autophagy flux cannot always be reliably detected during induction, complicating patient stratification and therapeutic timing. - Some combinations (e.g., AraC with autophagy inhibitors in AML) do not produce additive cytotoxic effects, indicating that autophagy-targeting strategies may not universally enhance therapy. - As a narrative overview/summary of a Special Issue rather than a systematic study, standardized methodologies and comprehensive bias assessments are not provided.