Mapping therapy-responsive immune ecotypes in clear cell renal cell carcinoma through integrative omics.

Clear cell renal cell carcinoma (ccRCC) is a kidney cancer in which immune activity is closely intertwined with von Hippel-Lindau (VHL) loss, hypoxia-inducible factor (HIF) signaling, angiogenesis, hypoxia, and metabolic adaptation. Although immune checkpoint inhibitor (ICI)-based regimens have changed the treatment landscape of advanced ccRCC, only a subset of patients achieve durable benefit. Commonly used biomarkers, such as programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), and broad inflammatory gene signatures, have not been sufficient to explain this variation or to guide routine treatment selection. One reason is that immune infiltration in ccRCC is not synonymous with effective antitumor immunity. A tumor rich in CD8+ T cells may still be resistant if these cells are exhausted, metabolically restricted, spatially separated from tumor nests, or surrounded by suppressive myeloid, stromal, and vascular programs. Therefore, the key issue is not simply whether a tumor is immunologically "hot" or "cold," but which part of the antitumor response has failed. In this Mini Review, we discuss ccRCC immunotherapy response from an immune-ecological perspective. We focus on several treatment-relevant immune states, including T-cell-inflamed but dysfunctional tumors, myeloid-dominant suppressive tumors, angiogenesis- and hypoxia-skewed tumors, and immune-excluded tumors. We also consider how bulk transcriptomics, single-cell and spatial profiling, T-cell receptor sequencing, proteomics, metabolomics, and longitudinal liquid biopsy may help define these ecotypes and capture treatment-induced remodeling. This perspective may support more refined patient stratification and more mechanism-matched immunotherapy strategies in ccRCC.