Essential genetic mutations impair DNA damage repair and modulate tumor immune microenvironment in ccRCC

Targeting DNA repair defects has shown therapeutic benefits in solid tumors with genetic mutations that disrupt DNA damage repair (DDR) pathways. Clear cell renal cell carcinoma (ccRCC) demonstrates an intermediate level of genomic instability, while it rarely carries mutations in these genes. Instead, it is characterized by the loss of chromosome 3p, the von Hippel-Lindau (VHL) tumor suppressor gene inactivation, and secondary mutations in Polybromo-1 (PBRM1), SET domain-containing 2 (SETD2), and BRCA-associated protein 1 (BAP1). Here, we summarize and discuss how these essential mutations impair the DDR, activate the cytosolic DNA sensing pathway, alter the tumor immune microenvironment, and offer promising therapeutic targets.