{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:35:55Z","timestamp":1789644955801,"version":"4.0.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The clinical translation of prostate-specific membrane antigen (PSMA)-directed chimeric antigen receptor (CAR) T-cell therapy for metastatic castration-resistant prostate cancer (mCRPC) has reached a critical impasse. Despite compelling preclinical rationale and early biological activity, durable clinical responses remain scarce, constrained by three core solid tumor challenges: a profoundly immunosuppressive\/metabolically hostile tumor microenvironment (TME), pervasive antigen heterogeneity driving immune escape, and intrinsic limitations in T-cell fitness and\n                    <jats:italic>in vivo<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1819701","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T05:46:38Z","timestamp":1776231998000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["PSMA-directed CAR-T cell therapy for metastatic castration-resistant prostate cancer: a next-generation engineering perspective on stem cell-derived immune effectors"],"prefix":"10.3389","volume":"17","author":[{"given":"Meng","family":"Zhang","sequence":"first","affiliation":[{"name":"Tongde Hospital of Zhejiang Province","place":["Hangzhou, China"]},{"name":"Zhejiang Academy of Traditional Chinese Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Li","sequence":"additional","affiliation":[{"name":"Tongde Hospital of Zhejiang Province","place":["Hangzhou, China"]},{"name":"Zhejiang Academy of Traditional Chinese Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaisen","family":"Liao","sequence":"additional","affiliation":[{"name":"Tongde Hospital of Zhejiang Province","place":["Hangzhou, China"]},{"name":"Zhejiang Academy of Traditional Chinese Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J 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