PSMA-CAR-T Cells for Metastatic Castration-Resistant Prostate Cancer: An Integrated Framework for Translational Optimization

Background Metastatic castration-resistant prostate cancer (mCRPC) portends a poor prognosis and represents an area of urgent unmet clinical need. The high, specific overexpression of prostate-specific membrane antigen (PSMA) on tumor cells provides a compelling rationale for targeted immunotherapy. However, the translation of PSMA-directed chimeric antigen receptor T (CAR-T) cell therapy from bench to bedside faces substantial barriers typical of solid tumors. Main body This review offers a comprehensive translational perspective on PSMA-targeted CAR-T therapy for prostate cancer. This review first delineates the biological rationale for PSMA and the evolution of CAR designs, then synthesizes early-phase clinical trial data, highlighting preliminary efficacy while delineating key translational gaps—including a suppressive tumor microenvironment, antigen heterogeneity, and T-cell exhaustion. To address these gaps, we propose an integrated optimization framework built on three synergistic pillars : (1) precision CAR engineering (e.g., logic-gated constructs, safety switches); (2) remodeling the tumor microenvironment (e.g., armored CAR-T cells, rational combinations); and (3) innovating manufacturing and delivery (e.g., allogeneic products, enhanced persistence). We further analyze overarching translational bottlenecks in preclinical modeling and trial design, proposing actionable solutions to accelerate clinical integration. Conclusions PSMA-targeted CAR-T therapy holds transformative potential for mCRPC but remains at a pivotal translational juncture. To realize this potential, an integrated strategy is imperative: advancing next-generation CAR designs, deploying intelligent combination regimens, streamlining cell manufacturing, and fostering predictive preclinical models alongside collaborative, biomarker-driven clinical trials. Through such concerted efforts, this modality can evolve from a promising investigational approach into an effective pillar of the prostate cancer treatment arsenal.