• Clear Cell Renal Cell Carcinoma in the Modern Era: A Review of Evolving Targeted and Combination Therapies from 2020 to 2025
  • Fatemeh Fayaz Sarcheshmeh,1,*
    1. Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University.


  • Introduction: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), accounting for 70–80% of cases and contributing significantly to cancer-related deaths worldwide. Although advances in early detection and surgery have improved outcomes for some, many patients are still diagnosed at advanced or metastatic stages, where prognosis remains unfavorable. This review explores recent developments in ccRCC treatment, with an emphasis on targeted therapies, vascular endothelial growth factor inhibitors (VEGFIs), mammalian target of rapamycin inhibitors (mTORIs), tyrosine kinase inhibitors (TKIs), and immune checkpoint inhibitors (ICIs), used both individually and in combination.
  • Methods: A systematic search was conducted in the PubMed database on May 23, 2025, using Boolean operators applied to the title and abstract fields containing keywords such as “clear renal cell carcinoma,” “targeted therapy,” “VEGFIs,” “mTORIs,” “TKIs,” and “ICIs.” The search was limited to publications from 2020 to 2025, yielding 47 articles. After screening for relevance to targeted monotherapy or combination therapy, 11 studies met the inclusion criteria and were selected for detailed analysis.
  • Results: Targeted therapies, including VEGF and mTOR inhibitors, have proven effective in managing ccRCC. TKIs such as sunitinib and pazopanib have improved progression-free survival (PFS), although resistance and adverse effects remain significant challenges. ICIs, including nivolumab, pembrolizumab, and atezolizumab, enhance the immune response by blocking the PD-1/PD-L1 pathway, thereby improving overall survival (OS) and objective response rates (ORR). Combination therapies, particularly those combining ICIs with TKIs, have demonstrated superior outcomes compared to monotherapy and are now considered the standard first-line treatment for advanced ccRCC.
  • Conclusion: Targeted and immune-based therapies have transformed ccRCC treatment, particularly for patients with advanced or inoperable disease. While drug resistance remains a challenge, continued research is refining treatment strategies and moving toward more personalized, effective care options that offer improved outcomes and hope for long-term survival.
  • Keywords: Renal cell Carcinoma, Cancer treatment, Targeted therapy, Cancer immunotherapy, Combination therapy.