Intratumoral mycobiome heterogeneity influences the tumor microenvironment and immunotherapy outcomes in renal cell carcinoma.

The intratumoral mycobiome plays a crucial role in the tumor microenvironment, but its impact on renal cell carcinoma (RCC) remains unclear. We collected and quantitatively profiled the intratumoral mycobiome data from 1044 patients with RCC across four international cohorts, of which 466 patients received immunotherapy. Patients were stratified into mycobiota ecology-depauperate and mycobiota ecology-flourishing (MEF) groups based on fungal abundance. The MEF group had worse prognosis, higher fungal diversity, down-regulated lipid catabolism, and exhausted CD8+ T cells. We developed the intratumoral mycobiota signature and intratumoral mycobiota-related genes expression signature, which robustly predicted prognosis and immunotherapy outcomes in RCC and other cancers. Aspergillus tanneri was identified as a potential key fungal species influencing RCC prognosis. Our findings suggest that the intratumoral mycobiome suppresses lipid catabolism and induces T cell exhaustion in RCC.