The differentiation and functional landscape of tumor-resident CD8 ⁺ T cells shapes immunity and clinical outcomes in clear cell renal cell carcinoma

Abstract Clear cell renal cell carcinoma (ccRCC) is a common and lethal kidney cancer in which CD8 + T cell–targeted immunotherapies are standard of care. However, tumor CD8 + T cell infiltration correlates with divergent clinical outcomes, reflecting functional heterogeneity. We comprehensively characterized tumor-specific memory CD8 + T cells in ccRCC using phenotypic, transcriptional and functional analyses. Three major subsets were identified based on tissue-residency markers: circulating (Tcirc), tissue-resident (Trm) and CD69 + CD103 − Trm-like cells, all recognizing autologous RCC cells in an HLA class I–dependent manner. Tcirc cells exhibited greater stemness and cytotoxic potential, whereas Trm populations displayed tissue-residency programs, enhanced tumor reactivity and exhaustion features. Single-cell transcriptomics analyses uncovered substantial heterogeneity within Trm cells, including progenitor, activated, transitional, type-17, interferon-responsive, regulatory and terminally exhausted states. Trajectory and TCR analyses indicated progressive differentiation from central-memory Tcirc cells toward tissue residency while losing circulation, cytotoxicity and stemness potentials and then progress toward terminal exhaustion. Enrichment of progenitor Trm cells associated with improved survival and favorable immunotherapy response, whereas regulatory or exhausted Trm cells correlated with poor outcomes. These findings define the differentiation and functional landscape of tumor-specific CD8 + T cells that shapes immunity and clinical outcomes in ccRCC.