Comprehensive review compares ICI-based regimens and ICI-TKI combinations against sunitinib in metastatic renal cell carcinoma.

This review examines the evolving first-line immunotherapy landscape in metastatic renal cell carcinoma (mRCC), with emphasis on the comparative clinical logic of dual immune checkpoint blockade (ICI-ICI) and immune checkpoint inhibitor-tyrosine kinase inhibitor combinations (ICI-TKI), the persistent efficacy-effectiveness gap, biomarker development, and translational resistance biology. Pivotal phase III trials have established superior survival for contemporary ICI-based regimens over sunitinib; however, cross-trial heterogeneity, differences in IMDC risk distribution, varying toxicity profiles, and selection of fitter trial populations complicate simple regimen ranking. Real-world studies confirm that outcomes in routine practice are frequently less favorable than those reported in registration studies, but these differences are partly explained by confounding related to performance status, comorbidity burden, access to care, toxicity management, and treatment sequencing. Renal cell carcinoma remains a biomarker-challenged disease in which PD-L1 and tumor mutational burden have limited predictive value, while PBRM1 status, VHL-driven pseudohypoxia, and spatial immune architecture are biologically informative but not yet clinically validated as stand-alone selection tools. Resistance arises through tumor-intrinsic metabolic reprogramming, impaired antigen presentation, compensatory checkpoint signaling, and stromal-myeloid exclusion within the tumor microenvironment. Taken together, the field is moving from empirical regimen selection toward a model that integrates disease tempo, patient fitness, translational biomarkers, and mechanism-based sequencing. Future progress will depend on composite biomarker validation, biomarker-enriched trials, rational resistance-directed combinations, and structural measures that improve external validity and equitable access.