The role of pathology in immunotherapy and targeted therapy for renal cell carcinoma

Purpose of review: This review outlines a pathology-driven framework that integrates morphology, immunophenotype, and molecular profiling to inform personalized treatment strategies in renal cell carcinoma (RCC), particularly with immunotherapy and tyrosine kinase inhibitors (TKIs). Recent findings: Systemic therapy for RCC has progressed from cytokine-based regimens to VEGF-targeted TKIs and, more recently, immune checkpoint inhibitors (ICIs), alone or in TKI combinations, resulting in improved survival. Yet, reliable predictive biomarkers remain an unmet need. Programmed death-ligand 1 (PD-L1) expression, while biologically relevant, offers limited clinical utility, as ICI responses occur in both PD-L1-positive and -negative tumors. Tumor microenvironment features (e.g., T-effector and myeloid inflammation signatures) and genomic alterations (e.g., PBRM1 , BAP1 , SETD2 ) provide biological and prognostic insights, but have inconsistent predictive value. Summary: Pathology remains essential for accurate histologic classification, grading, and assessment of adverse features such as sarcomatoid changes and necrosis. Molecular profiling is increasingly helpful in non-clear cell RCC, guiding targeted therapies in subtypes such as MET-driven papillary RCC. Emerging tools (liquid biopsy, spatial transcriptomics, and AI-assisted pathology) offer minimally invasive monitoring, refined immune profiling, and multiparametric biomarker integration to advance precision oncology in RCC.