Evolution of Systemic Therapy in Metastatic Renal Cell Carcinoma: From Cytokines to Immune Checkpoint Inhibitors and HIF-2α Targeted Therapy

Thiruvarul P V, Ezhil Sundar V, Chengalvarayan G, Tamil Selvan R

Abstract: Metastatic renal cell carcinoma (mRCC) has undergone a remarkable therapeutic transformation over the past three decades. Initially, treatment relied on cytokine-based immunotherapy with interferon-alpha (IFN-α) and high-dose interleukin-2 (HD IL-2), which produced durable responses in a small subset of patients but were associated with substantial toxicity. Advances in understanding the molecular biology of clear-cell renal cell carcinoma (ccRCC), particularly the role of von Hippel-Lindau (VHL) gene inactivation and hypoxia-inducible factor (HIF) signaling, led to the development of vascular endothelial growth factor (VEGF)-targeted therapies and mammalian target of rapamycin (mTOR) inhibitors. Although these agents significantly improved progression-free survival, durable complete responses remained uncommon. The advent of immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) revolutionized the management of mRCC and now forms the foundation of contemporary treatment. Landmark clinical trials including CheckMate 025, CheckMate 214, KEYNOTE-426, CheckMate 9ER, and CLEAR have demonstrated significant improvements in survival and durable disease control. More recently, HIF-2α inhibition with belzutifan has emerged as a novel therapeutic strategy directly targeting the molecular drivers of ccRCC. This review summarizes the evolution of systemic therapy in RCC, emphasizing immune checkpoint blockade, immunotherapy-based combinations, emerging therapeutic approaches, and future directions in precision immuno-oncology (1-10).

Keywords: Renal cell carcinoma, metastatic renal cell carcinoma, immune checkpoint inhibitors, immunotherapy, PD-1, CTLA-4, belzutifan, HIF-2&alpha,

How to Cite?: Thiruvarul P V, Ezhil Sundar V, Chengalvarayan G, Tamil Selvan R, "Evolution of Systemic Therapy in Metastatic Renal Cell Carcinoma: From Cytokines to Immune Checkpoint Inhibitors and HIF-2α Targeted Therapy", Volume 15 Issue 7, July 2026, International Journal of Science and Research (IJSR), Pages: 1863-1873, https://www.ijsr.net/getabstract.php?paperid=SR26723014950, DOI: https://dx.doi.org/10.21275/SR26723014950

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