Repurposing Antipsychotics in Cancer Therapy: Modulation of Autophagy Mechanisms.

Abstract

Antipsychotic drugs, long established in the management of psychotic disorders, are increasingly recognized as modulators of autophagy with potential implications for cancer therapy. A growing body of evidence demonstrates that several antipsychotics, such as phenothiazines and penfluridol, can regulate autophagic flux in tumor cells, thereby affecting cell survival, apoptotic signaling, and responsiveness to anticancer treatments. Autophagy is a fundamental homeostatic process that enables tumor cells to meet heightened metabolic demands and adapt to diverse cellular stresses; however, its dysregulation can also facilitate therapeutic resistance. Pharmacological modulation of this pathway by antipsychotics may therefore enhance tumor sensitivity to conventional therapies and contribute to overcoming drug resistance. Importantly, the effects of these agents on autophagy are context dependent, varying with drug class, concentration, and tumor type, and can lead to divergent outcomes in tumor growth and progression. Drawing on accumulating preclinical and emerging clinical evidence, the current review delineates the molecular basis of antipsychotic-autophagy crosstalk and highlights the promise of repurposing these agents as adjunctive strategies in cancer treatment, while underscoring the need for rigorous mechanistic and translational investigations.