Our finding of VHL gene loss causing constitutive activation of the cGAS-STING signaling and increased intratumoral lymphocyte infiltration (Graphic Abstract) provides critical insights into how ccRCC with moderate TMB unexpectedly responds well to ICB therapy,58,59 despite the discrepancy that several published clinical studies did not show an improved response to ICB treatment in patients with VHL-mut ccRCC. This evidence concerns the gene CGAS and nonpapillary renal cell carcinoma.