{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T15:43:18Z","timestamp":1783093398450,"version":"3.54.6"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"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>Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of hematologic malignancies, yet its clinical efficacy in solid tumors remains limited. Renal cell carcinoma (RCC) presents a striking paradox: despite its established responsiveness to immune modulation and the expression of targetable tumor antigens, CAR-T therapies have failed to produce durable clinical benefit. This failure has often been attributed to antigen heterogeneity or lack of tumor specificity; however, accumulating clinical and experimental evidence suggests that antigen recognition alone does not determine therapeutic success in RCC. In this review, we discuss evidence that CAR-T failure in RCC may reflect consistent biological constraints suggesting a systemic mismatch between engineered T cells and the renal tumor ecosystem. Across clinical studies targeting multiple RCC-associated antigens, CAR-T cells demonstrate limited tumor trafficking, rapid functional decline, and poor intratumoral persistence, with little evidence of antigen-driven escape. We examine three interrelated barriers underlying this failure: immune exclusion driven by abnormal vasculature, hypoxia, and suppressive myeloid populations; profound metabolic competition and bioenergetic stress imposed by the uniquely rewired RCC microenvironment; and the insufficiency of antigen targeting in the absence of environmental support for sustained T cell function. We further discuss how these insights necessitate a shift from generic CAR-T platforms toward RCC-adapted cellular therapies. Strategies that enhance tumor homing, improve metabolic fitness, tolerate hypoxia, and actively remodel the myeloid-dominated microenvironment may be essential for achieving durable efficacy. Finally, we outline implications for clinical trial design, patient selection, and biologically rational combination strategies. Reframing CAR-T therapy as a systems-level intervention, rather than a target-restricted cytotoxic approach, may be critical for unlocking its potential in renal cell carcinoma.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1828738","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:48:32Z","timestamp":1781156912000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Why CAR T cell therapy fails in renal cell carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Hua-jun","family":"Zhang","sequence":"first","affiliation":[{"name":"Yuyao Hospital of Traditional Chinese Medicine","place":["Ningbo, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lv-zhou","family":"Han","sequence":"additional","affiliation":[{"name":"Yuyao Hospital of Traditional Chinese Medicine","place":["Ningbo, Zhejiang, 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