Chemical Carcinogenesis in Clear Cell Renal Cell Carcinoma: A Comprehensive Review of Environmental Risk Factors, Mechanisms, and Clinical Implications

Renal cell carcinoma (RCC), particularly clear cell renal cell carcinoma (ccRCC), presents a growing global health burden with increasing incidence. While established risk factors exist, environmental and occupational chemical exposures are increasingly recognized as significant contributors. This review systematically synthesizes literature on the association between chemical exposures (e.g., trichloroethylene, cadmium, asbestos, pesticides, PFAS, benzene) and ccRCC development. Epidemiological evidence reveals elevated ccRCC incidence in exposed populations, often with distinct geographic and occupational clusters, and demographic disparities. Mechanistically, chemical carcinogens drive ccRCC through direct DNA damage, epigenetic alterations (DNA methylation, miRNA dysregulation), chronic inflammation, fibrosis, and disruption of the VHL-HIF pathway, leading to metabolic reprogramming. Chemically induced tumors often exhibit more aggressive biological behavior and distinct molecular signatures (e.g., VHL, PBRM1, SETD2, BAP1 mutations; NRF2–KEAP1 activation), influencing prognosis and treatment responsiveness. Prevention strategies include stricter occupational regulations, but challenges remain in early detection due to long latency and lack of specific biomarkers. Comprehensive occupational health surveillance and integrated therapeutic approaches targeting these mechanistic pathways are crucial for mitigating the impact of chemical carcinogenesis on ccRCC.