Targeting autophagy-dependent cell death in cancer therapy: An update on small-molecule compounds.

Autophagy-dependent cell death (ADCD) is a regulated form of cell death that relies on the autophagic machinery. This review provides a systematic update on the landscape of small-molecule compounds that induce ADCD in cancer. We discuss core autophagy-related proteins and the role of autophagic flux in determining lethal outcomes. Compounds are classified by mechanism: inhibitors of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis, activators of the AMP-activated protein kinase (AMPK)/unc-51 like autophagy activating kinase 1 (ULK1) axis, endoplasmic reticulum stress inducers, and epigenetic modulators. Translational barriers are addressed, including the context-dependent dual role of autophagy and the lack of predictive biomarkers. Emerging strategies such as nanocarrier-based delivery and combination therapies are discussed. We also propose experimental criteria for ADCD identification and highlight future directions including artificial intelligence-assisted discovery and multi-omics approaches for patient stratification.