TMC8 is associated with a paradoxical immune landscape and promotes clear cell renal cell carcinoma progression

Abstract

Clear cell renal cell carcinoma (ccRCC) progression is closely linked to a complex tumor microenvironment (TME), yet key regulators remain unclear. This study aimed to systematically investigate the roles of TMC8 in ccRCC, focusing on its immunological and biological potential. Multi-cohort transcriptomic data were integrated to analyze TMC8 expression and prognostic value. Functional enrichment and multiple immune deconvolution algorithms were applied to characterize TME associations. Single-cell RNA sequencing (scRNA-seq) analysis characterized TMC8 -associated transcriptional features across immune-cell populations. Sex-stratified analyses were performed to identify dimorphic effects. In vitro and in vivo experiments were conducted to validate the biological functions of TMC8 . TMC8 was significantly upregulated in ccRCC and associated with poor overall survival, particularly in males. Its expression correlated with higher estimated immune infiltration and antigen-presentation-related signatures, alongside elevated expression of exhaustion-associated markers. scRNA-seq analysis suggested the uncoupling of T-cell activation and effector competence. Notably, TMC8 exhibited marked sex-specific associations, with stronger oncogenic and immunological associations in males. Functionally, TMC8 promoted tumor progression by enhancing proliferation, migration, and invasion, which were suppressed upon TMC8 knockdown in vitro and in vivo . TMC8 is associated with dysregulated oncogenic signaling and an immunologically active yet dysfunctional TME in ccRCC, with pronounced sex-specific associations, and may represent a putative therapeutic target warranting further validation.