Repurposing Antipsychotic Agents in Oncology: Mechanistic Rationale, Emerging Evidence, and Therapeutic Potential.

Antipsychotic agents-spanning first-, second-, and third-generation drug classes-are emerging as mechanistically diverse candidates for repurposing in oncology. Although developed to modulate dopaminergic and serotonergic neurotransmission, some of these compounds exert pleiotropic effects on cancer cell survival, metabolism, and stemness. Across multiple malignancies, antipsychotics disrupt oncogenic signaling networks including PI3K/Akt/mTOR, STAT3/5, MAPK/ERK, and Wnt/β-Catenin, impair lysosomal and autophagic flux, and induce mitochondrial and calcium-dependent metabolic stress. Notably, several phenothiazines and dopamine-modulating agents selectively reduce cancer stem cell populations, suggesting potential utility in limiting recurrence and mitigating therapeutic resistance. These effects appear to involve disruption of CSC signaling pathways and interference with dopamine-dependent mechanisms that support stemness and survival. Preclinical studies consistently demonstrate antiproliferative, proapoptotic, antimetastatic, and chemosensitizing effects, whereas early clinical investigations demonstrate target engagement and feasibility but do not establish anticancer efficacy. Clinical trials of thioridazine in acute myeloid leukemia and chlorpromazine in glioblastoma show evidence of pharmacodynamic activity in patients, though these findings remain preliminary and non-efficacy-based. However, translation remains constrained by dose-limiting toxicities, pharmacokinetic barriers, and conflicting epidemiologic signals regarding long-term carcinogenic risk. Here, we synthesize mechanistic, translational, and emerging clinical findings relevant to antipsychotic repurposing in oncology, highlight tumor contexts in which these agents may hold potential, and outline future directions including biomarker-guided patient selection, rational combination strategies, and artificial intelligence (AI)-enabled drug-repurposing pipelines. Collectively, antipsychotics represent a promising yet underexplored class of multi-targeted agents; to define their full therapeutic potential will require rigorous mechanistic validation and carefully designed clinical trials.