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.
Oncogene. 2026 Jul 20 [Epub ahead of print]
Keying Li, Heng Du, Yifan Wang, Damir Khabibullin, Michel Alchoueiry, Melissa Daou, John M Asara, David J Kwiatkowski, Elizabeth P Henske, Heng-Jia Liu
Department of Colorectal Surgery of Sir Run Run Shaw Hospital, and Centre for Infection, Immunity and Cancer of Zhejiang University-University of Edinburgh Institute (ZJE), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, PR China., Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, PR China., Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA., Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. ., Department of Colorectal Surgery of Sir Run Run Shaw Hospital, and Centre for Infection, Immunity and Cancer of Zhejiang University-University of Edinburgh Institute (ZJE), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, PR China. .