Converting cold to hot: Strategies to sensitize microsatellite-stable colorectal cancer to immunotherapy

Figure 1 Immunobiology of “cold” microsatellite-stable/mismatch repair-proficient colorectal cancer and multilevel barriers to immune checkpoint blockade. Concentric layers summarize how tumor cell-intrinsic programs, the local tumor microenvironment (TME), and systemic gut-liver crosstalk converges to generate an immune-excluded, immune checkpoint inhibitor (ICI)-refractory phenotype in microsatellite-stable (MSS) colorectal cancer (CRC). Tumor cell-intrinsic mechanisms include low tumor mutational burden and limited neoantigenicity, impaired antigen processing/presentation (e.g., β2-microglobulin or Janus kinase/signal transducer and activator of transcription pathway alterations), and oncogenic signaling (Wnt/β-catenin and KRAS/BRAF/mitogen-activated protein kinase) that reduces cluster of differentiation 8⁺ T-cell infiltration and promotes programmed death ligand-1 upregulation and immune evasion; tumor- and stroma-derived transforming growth factor-β (TGF-β) further reinforces immune suppression and exclusion. In the TME, dense cancer-associated fibroblast-rich desmoplastic stroma increases tissue stiffness and forms a physical barrier, while aberrant vasculature and hypoxia impair T-cell trafficking. Immunosuppressive populations including myeloid-derived suppressor cells and M2-like tumor-associated macrophages producing interleukin-10, TGF-β, and arginase-1, along with regulatory T cells blunt effector function. Metabolic stress (glycolysis-driven lactate accumulation and acidic potential of hydrogen) further suppresses T-cell activity. At the systemic/gut-liver axis level, dysbiotic microbiota (e.g., Fusobacterium and enterotoxigenic Bacteroides fragilis) and microbiota-derived metabolites (bile acids, short-chain fatty acids, and tryptophan-kynurenine pathway products) reshape systemic immunity and therapeutic responsiveness; the tolerogenic liver niche promotes immune privilege of liver metastases. Collectively, these factors yield a composite immune-cold state characterized by scarce functional T cells, dominant immunosuppressive myeloid/stromal elements, and microbiome-linked resistance, underpinning primary non-response to ICIs in MSS CRC. TMB: Tumor mutational burden; TME: Tumor microenvironment; B2M: Β2-microglobulin; JAK/STAT: Janus kinase/signal transducer and activator of transcription; MAPK: Mitogen-activated protein kinase; PD-L1: Programmed death-ligand 1; CD: Cluster of differentiation; TGF-β: Transforming growth factor-β; ARG1: Arginase-1; MDSC: Myeloid-derived suppressor cell; IL: Interleukin; CAF: Cancer-associated fibroblast; TAM: Tumor-associated macrophage; SCFA: Short-chain fatty acid; ETBF: Enterotoxigenic Bacteroides fragilis.