APOE+ macrophages and POSTN+CAFs form immune-exclusion niche driving immunotherapy resistance in clear-cell renal carcinoma.

Tumor immune barriers (TIBs) are spatially organized stromal-immune niches that restrict lymphocyte entry. To explain persistent immune-checkpoint blockade (ICB) resistance in clear cell renal cell carcinoma (ccRCC), we mapped TIBs and defined a peritumoral variant built from POSTN+ cancer-associated fibroblasts (CAFs) interlaced with APOE+ tumor-associated macrophages (TAMs). This niche excluded CD8+ T cells from tumor cores, and was enriched in poor-prognosis, ICB-refractory patients. Spatial transcriptomics and single-cell profiling showed TIB regions enriched for extracellular-matrix remodeling, immunosuppressive ligand-receptor circuits, and metabolic reprogramming. Mechanistically, tumor-derived TGF-β1 activated CAFs via SMAD signaling, inducing POSTN and recruiting APOE+TAMs through integrin and chemokine axes. TAMs secreted TGF-β1 and VEGFA, amplifying stromal programs and sustaining exclusion. Blocking POSTN reprogrammed macrophages, reduced matrix-mediated suppression, and restored CD8+ infiltration. In vivo, POSTN inhibition combined with ICB boosted antitumor immunity, reduced tumor burden, and reversed immunosuppressive infiltration, nominating POSTN-directed strategies to potentiate ICB.