Chromophobe renal cell carcinoma: Emerging vulnerabilities as a promise for a new therapeutic landscape.

Chromophobe renal cell carcinoma (ChRCC) is a rare tumor and the third most common subtype of renal cell carcinoma and is characterized by low tumor mutational burden, mitochondrial abnormalities, and distinct metabolic dependencies. Historically grouped under non-clear cell renal cell carcinoma and often excluded from histology-specific trials or lumped into basket trials, ChRCC has long lacked tailored therapeutic options. Recent efforts have begun to bring to light its specific biology and therapeutic vulnerabilities. This review summarizes emerging data from clinical trials, including recent studies evaluating immune checkpoint and tyrosine kinase inhibitors, and highlights their variable efficacy in ChRCC. We then describe three promising therapeutic avenues based on ChRCC-specific features: (1) ferroptosis induction through glutathione homeostasis disruption, (2) antibody-drug conjugates targeting KIT, and (3) natural killer adoptive cell therapy. This review underscores the need for continued multiprofessional collaboration to transform basic science discoveries into improved outcomes for ChRCC patients via inclusive and biology-informed trials.