mTORC1 activation induces B7-H3–dependent metabolic reprogramming in renal cell carcinoma (RCC)

Renal cell carcinoma (RCC) affects over 435,000 people worldwide each year and remains a significant cause of cancer mortality. Aberrant activation of pathways such as mTORC1 is frequently observed in RCC, yet the mechanisms by which mTORC1 contributes to tumor development remain poorly understood. The lack of suitable animal models has limited progress in uncovering these mechanisms and advancing targeted treatments. Here, we performed single-cell transcriptomic, proteomic, and metabolomic profiling of kidneys from mice with embryonic Tsc2 deletion at E17.5, which revealed a distinct tumor cell population characterized by intercalated cell signatures, co-expression of Foxi1 and Rhcg, and hyperactivated mTORC1. These lesions closely resemble human chromophobe renal cell carcinoma (ChRCC), a subtype of RCC. The tumors show marked upregulation of the immune checkpoint molecule B7-H3. Mechanistically, the transcription factor NRF1 is elevated in Tsc2-deficient lesions and drives B7-H3 expression in tumor cells. In human specimens, B7-H3 is broadly expressed in both classical and sarcomatoid ChRCC and correlates with hallmark markers FOXI1, MUC2, and HEPACAM2. Strikingly, B7-H3 deletion in mice suppresses Tsc2 loss–driven cystic and tumor formation, restores amino acid metabolism, and attenuates aminoacyl-tRNA biosynthesis and proteasome activity. Collectively, these findings identify B7-H3 as a functional driver of Tsc2-mediated ChRCC and a promising therapeutic target in TSC-associated renal tumors.