LIMD2 is associated with an exhausted CD8⁺ T cell state linked to ICI response in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is characterized by abundant infiltration of CD8⁺ T cells; however, the clinical benefit from immune checkpoint inhibitors (ICI) remains limited. To clarify this paradox, we systematically investigated the functional states of CD8⁺ T cells in ccRCC, with a particular focus on exhaustion-associated subsets and their potential link to ICI responsiveness. By integrating six publicly available bulk and single-cell RNA sequencing datasets with independent institutional validation cohorts, we found that the majority of tumor-infiltrating CD8⁺ T cells exhibited an exhausted phenotype, characterized by elevated expression of canonical exhaustion markers. Importantly, we identified CD8⁺ T cells with high LIM domain-containing protein 2 (LIMD2) expression that co-express canonical exhaustion markers and are enriched in ICI responders. Single-cell transcriptomic analyses further supported markedly increased LIMD2 expression within CD8⁺ Tex cells from patients achieving clinical benefit. Multiplex immunofluorescence showed LIMD2 protein predominantly localized to CD8A⁺ T cells, co-expressed with exhaustion markers, and significantly enriched in tumor tissues of responders. Collectively, these findings indicate that CD8⁺ Tex cells with high LIMD2 expression are associated with ICI responses in ccRCC, positioning LIMD2 as a candidate predictive biomarker to refine patient stratification and inform immunotherapy optimization.