Multicellular immunosuppressive networks in microsatellite-stable colorectal cancer: CD8+ T cell exclusion, dysfunction, exhaustion, and therapeutic implications.

Microsatellite-stable (MSS) colorectal cancer (CRC), comprising ~85-90% of cases, remains almost universally refractory to PD-1/PD-L1 monotherapy (objective response rate 5-10%), in stark contrast to the marked efficacy of immune checkpoint inhibitors (ICIs) in microsatellite-instability-high (MSI-H) disease. Here we synthesize evidence that CD8+ T cell exclusion, dysfunction, and exhaustion in MSS CRC are orchestrated not by cell-autonomous failures but by a multicellular immunosuppressive network in which tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) cooperate through mechanistically distinct yet spatially integrated axes. We propose a four-layer hierarchical model (physical exclusion, effector dysfunction, metabolic deprivation, and active suppression) that culminates in a stereotyped three-layer spatial niche best documented in CRC liver metastases (outer mCAF belt, Tex/TSTR band, inner SPP1+ TAM aggregates). MSS-associated mechanisms include the TAM-derived COX2/PGE2/TIGIT axis driving terminal exhaustion, a functional IL-10-/IL-10+ Treg dichotomy, and CAF-mediated suppression of dendritic-cell CXCL9/10 production that blocks CXCR3+ CD8 recruitment. Effective therapeutic strategies must therefore target multiple layers simultaneously, including TAM reprogramming, stromal remodeling, precision Treg depletion, and MDSC differentiation, rather than relying on additional checkpoint inhibitors, which have proven insufficient as monotherapy or in dual combinations.