A Tertiary Lymphoid Structure–Derived Prognostic Signature Integrates Immune Microenvironment and Mutational Landscapes in Clear Cell Renal Cell Carcinoma

Tertiary lymphoid structures (TLSs) are increasingly recognized as important components of the tumor immune microenvironment, yet their prognostic and immunological implications in clear cell renal cell carcinoma (ccRCC) remain incompletely characterized. In this study, we performed an integrated bioinformatic and translational analysis to investigate TLS‐associated molecular features in ccRCC. Using TCGA‐KIRC transcriptomic data, we identified three TLS‐related molecular subtypes with distinct survival outcomes and immune microenvironment characteristics. Based on prognostic TLS‐associated genes, we developed a four‐gene TLS‐derived score (CSF2, CXCL13, IL1R2, and SGPP2) that stratified patients into groups with significantly different overall survival. The TLS score remained an independent prognostic factor after adjustment for clinical variables. Interestingly, higher TLS scores were associated with increased immune infiltration but poorer survival outcomes, suggesting that TLS‐associated transcriptional patterns may reflect heterogeneous immune functional states rather than uniformly effective antitumor immunity. Computational analyses indicated potential differences in predicted immunotherapy response and mutation landscapes between TLS score groups. Limited experimental validation using fresh ccRCC specimens supported the feasibility of TLS score assessment and provided preliminary histopathological context for TLS‐associated immune features. Overall, this study proposes a TLS‐derived transcriptional signature that may help capture immune heterogeneity in ccRCC and may provide a complementary framework for prognostic assessment. Further studies are required to validate its biological and clinical relevance.