From Therapeutic Drug to Xenobiotic in Cancer Repurposing: Clozapine Mechanisms, Metabolic Liabilities, and Human-Relevant Translational Approaches.

Drug repurposing represents a rational and resource-efficient strategy to expand the oncological armamentarium by leveraging the established pharmacology, clinical experience, and safety-monitoring frameworks of approved non-oncological agents. Clozapine (CZP), an atypical antipsychotic characterized by broad receptor pharmacology, complex biotransformation, and clinically relevant toxicological liabilities, has emerged as a candidate of interest following preclinical evidence of context-dependent anticancer activity across multiple tumor types. As such, CZP provides an informative case study at the interface between therapeutic drug action and xenobiotic behavior. This review provides a critical and integrated synthesis of the current evidence supporting the repurposing of CZP in oncology, with particular emphasis on the relationship between its molecular mechanisms, dose-exposure requirements, pharmacological complexity, and potential toxicity. Analysis of in vitro and in vivo studies across glioblastoma, non-small cell lung cancer, breast cancer, and melanoma brain metastasis models indicates that CZP can impair tumor cell proliferation and survival through a form of mechanistic plasticity. Rather than acting through a single conserved pathway, CZP appears to disrupt shared upstream processes related to pro-survival signaling, cellular stress tolerance, and metabolic homeostasis, while engaging tumor-specific downstream responses, including autophagic cell death, mitochondria-dependent apoptosis, oxidative stress, and coordinated modulation of survival and angiogenic pathways. Despite this mechanistic rationale, translation remains substantially constrained, most notably by the order of magnitude gap between anticancer-effective concentrations in vitro and clinically achievable plasma exposures, requiring careful distinction between potentially useful anticancer pharmacology and nonspecific xenobiotic-induced cellular stress and clinically unacceptable toxicity. Key limitations include the discrepancy between anticancer-effective concentrations observed in vitro and exposures achievable during standard psychiatric dosing, the limited understanding of how CZP metabolism and metabolite formation may influence efficacy and toxicity, the absence of integrated pharmacokinetic-pharmacodynamic and toxicokinetic modeling, and the lack of dedicated clinical trial evidence. To address these challenges, this review examines complementary translational strategies, including patient-derived organoids, co-culture systems, microphysiological platforms, pharmacokinetic and toxicological modeling, and computational digital twin frameworks. Together, these approaches may support a biologically informed and risk-aware evaluation of CZP, helping to identify responsive tumor contexts, anticipate exposure-related liabilities, and prioritize rational combination strategies. By integrating therapeutic potential with xenobiotic pharmacology and toxicology, this review positions CZP within the evolving landscape of precision oncology and evidence-driven drug repurposing.