Mechanisms of immunotherapy resistance in MSS CRC (IMAGE)
Caption
Created in BioRender.com. (a) Low neoantigen burden results in insufficient T-cell priming and activation. (b) An immunosuppressive tumor microenvironment underlies primary resistance in MSS CRC: ① Monocytes and Macrophages: Monocytes differentiate into distinct macrophage subsets; M2-polarized macrophages foster immune escape and tumor angiogenesis. Regulatory T cells (Tregs): Secrete immunosuppressive cytokines (IL-10, TGF-β), inhibit antitumor T-cell responses, and reprogram the microenvironment via fatty-acid accumulation and metabolic modulation. ② Myeloid-derived suppressor cells (MDSCs): Inhibit natural killer (NK) cell cytotoxicity and IFN-γ production, impairing NK-mediated activation of effector T cells; sustain immunosuppression through lipid-metabolism reprogramming. Neovasculature: Endothelial cells and tumor-associated vessels secrete VEGF, further dampening immune-cell infiltration and function. ③ Cancer-associated fibroblasts (CAFs): Resident fibroblasts, upon TGF-β stimulation, acquire a CAF phenotype that supports tumor growth and immune evasion. ④ Epithelial–mesenchymal transition (EMT): Tumor cells undergo phenotypic conversion, enhancing invasiveness and resistance to immune attack. CRC, colorectal cancer; IFN-γ, interferon-gamma; IL, interleukin; M-CSF, macrophage colony-stimulating factor; MHC1, major histocompatibility complex class I; MSS, microsatellite stable; PD-1, programmed cell death 1; PD-L1, programmed death ligand 1; TCR, T-cell receptor; TGF-β, transforming growth factor-beta; TMB, tumor mutational burden; VEGF, vascular endothelial growth factor.
Credit
Xiaochun Zhang
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