Drugging small-molecule compounds in autophagy-dependent cell death to overcome cancer therapy resistance.

Cancer therapy resistance remains a major challenge linked to metabolic rewiring, stress adaptation, and defective cell death. Autophagy is a lysosome-dependent process that can either promote tumor survival under stress or contribute to autophagy-dependent cell death (ADCD). Protective autophagy supports resistance through metabolic adaptation, organelle quality control, immune evasion, and maintenance of cancer stemness, whereas excessive or dysregulated autophagy may trigger lethal self-digestion. Emerging studies show that small molecules can reprogram autophagy from a survival pathway into a cytotoxic process by targeting AMPK/mTOR/ULK1 signaling, stress-response pathways, lysosomal function, and selective autophagy networks such as mitophagy and ferritinophagy. Importantly, ADCD can bypass apoptosis resistance, eradicate drug-tolerant persister cells, and enhance therapeutic efficacy in refractory tumors. This review outlines a mechanistic framework linking autophagy plasticity to therapy resistance, discusses pharmacological strategies for inducing ADCD, and highlights autophagy-to-lethality conversion as a promising therapeutic paradigm for overcoming resistance in refractory cancers while identifying future directions for clinical translation and rational combination therapies.