In two large phase III trials, JAVELIN Renal 101 and CheckMate-025, high MAEL expression was linked with anti-inflammatory TIME and VEGFR/mTOR activation in ccRCC tissues, high sensitivities to VEGFR/PI3K-AKT-mTOR inhibitors in ccRCC cell lines, and poor progression-free survival (PFS) benefits from ICI-based immunotherapies over VEGFR/mTOR inhibitors. The gene discussed is AKT1; the disease is nonpapillary renal cell carcinoma.