Purpose: Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, with many patients presenting with locally advanced or metastatic disease. Over the past decade, systemic therapy has evolved from cytokine-based regimens to targeted agents and immune checkpoint inhibitors (ICIs). Methods: A comprehensive narrative review was conducted of peer-reviewed literature and clinical trials published between 2008 and 2025, focusing on systemic therapies for advanced ccRCC, mechanisms of resistance, molecular imaging, and translational biomarker development. Results: Combination regimens integrating ICIs with vascular endothelial growth factor (VEGF), tyrosine kinase inhibitors (TKIs), or dual ICI therapies have significantly improved survival and represent current first-line standards. Emerging therapeutic categories include hypoxia-inducible factor-2α (HIF-2α) inhibitors, AXL/TYRO3/MER (TAM) receptor antagonists, radiopharmaceutical and theranostic platforms, and viral or cellular immunotherapies. Advances in molecular imaging, including carbonic anhydrase IX (CAIX) and prostate-specific membrane antigen (PSMA) targeted modalities, are improving detection and characterization of metastatic disease. Systemic and locoregional strategies are also being explored for biologically aggressive subsets, including tumors with inferior vena cava involvement. Despite these advances, resistance to VEGF-TKIs and ICIs persists, driving investigation into metabolic reprogramming, tumor microenvironment modulation, and emerging resistance pathways such as DEPDC1. Circulating tumor DNA (ctDNA), spatial transcriptomics, and artificial intelligence (AI) are increasingly integrated to support adaptive, precision-guided therapy. Conclusions: Modern ICI-based and biomarker-informed strategies have improved outcomes in metastatic ccRCC. Continued integration of translational biomarkers, ctDNA monitoring, and AI-driven analytics is expected to further personalize systemic therapy and enhance long-term disease control.
Castaneda et al. (Fri,) studied this question.