Navigating the landscape of targeted therapies for renal cell carcinoma in the era of precision medicine (Review)

Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy characterized by dysregulation of angiogenic signaling, immune evasion and epigenetic remodeling. Advances in molecular profiling have redefined RCC as a pathway‑driven disease, enabling the development of targeted therapies and immune checkpoint inhibitors (ICIs) that have notably improved clinical outcomes. The present review evaluated current evidence on the molecular basis and therapeutic landscape of RCC, with emphasis on von Hippel‑Lindau‑hypoxia‑inducible factor signaling, chromatin remodeling alterations and immune regulatory pathways. The present review summarizes pivotal phase III clinical trials evaluating VEGF‑targeted tyrosine kinase inhibitors, mechanistic target of rapamycin inhibitors, immune checkpoint inhibitors and combination regimens, including nivolumab plus ipilimumab, pembrolizumab + axitinib and lenvatinib + pembrolizumab. Emerging biomarkers, including International Metastatic Renal Cell Carcinoma Database Consortium risk stratification, programmed death‑ligand 1 expression and chromatin remodeling gene alterations (polybromo 1/BRG1‑associated factor 180, BRCA1‑associated protein 1 and SET domain containing 2), are discussed in the context of their clinical utility and limitations. Despite marked progress, durable predictive biomarkers and optimal treatment sequencing strategies remain unresolved. Resistance to therapy emerges through adaptive angiogenic signaling, immune escape and metabolic reprogramming, underscoring the need for integrated multi‑omics approaches and rational combination strategies. By integrating molecular biology with clinical trial evidence, the present review provides a structured framework for understanding therapeutic decision‑making in RCC and highlights future directions toward biomarker‑guided precision oncology.