PSMA-directed CAR-T cell therapy for metastatic castration-resistant prostate cancer: a next-generation engineering perspective on stem cell-derived immune effectors

persistence. This review synthesizes the current translational landscape (updated to February 2026), and posits a tripartite synergistic framework to systematically deconstruct these barriers: (1) advances in CAR synthetic biology; (2) active TME reprogramming via armored CAR-T cells, stromal-targeting agents, and rational combinations; (3) next-generation cellular product paradigms, with a focus on stem cell-derived immune effectors. Emerging platforms, including induced pluripotent stem cell (iPSC)-derived CAR-T, CAR-natural killer (NK) cells, and CAR-macrophages, offer unprecedented opportunities to overcome autologous product limitations via off-the-shelf availability, enhanced persistence, and intrinsic TME resistance. We further delineate a translational roadmap emphasizing biomarker-driven adaptive trials, predictive humanized preclinical models, and accessibility strategies. All core claims are graded using the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence to ensure academic rigor. This work provides a strategic blueprint to advance PSMA-CAR-T therapy toward curative-intent mCRPC treatment, with insights broadly applicable to next-generation stem cell-derived immunotherapies.