Pharmacologic HIF-2α inhibition preserves T cell transcriptome in clear cell renal cell carcinoma

Belzutifan is a selective HIF-2α inhibitor currently in clinical trials for clear cell renal cell carcinoma (ccRCC). As belzutifan is being evaluated in combination with immune checkpoint inhibitors, we investigated whether pharmacologic HIF-2α inhibition affects T cell transcriptional programs. Primary human pan T cells isolated from blood from healthy donors and ccRCC patients and tumor-infiltrating T cells were isolated from ccRCC patients. These cells were treated with belzutifan (2 μM, 5 days) vs. control DMSO under hypoxic conditions. RNA sequencing revealed that belzutifan treatment preserved T cell transcriptional programs, supporting the rationale for combining belzutifan with immunotherapy in ccRCC.