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

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).

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.

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.