Spatial immune architecture and immunotherapy resistance in microsatellite-stable colorectal cancer

Microsatellite-stable (MSS) colorectal cancer (CRC), which accounts for most metastatic CRC, remains largely resistant to immune checkpoint inhibitors. Although low tumor mutational burden and limited neoantigen generation contribute to this resistance, the spatial organization of the tumor microenvironment may also influence antitumor immunity. This review examines mechanisms that establish immune-resistant architectures in MSS CRC, including insufficient T-cell priming, oncogenic signaling, suppressive myeloid niches, hypoxia, abnormal vasculature, and fibroblast-driven extracellular matrix remodeling. We discuss candidate spatial biomarkers, including compartment-specific T-cell distribution, T-cell–tumor-cell distances, multicellular immune neighborhoods, perivascular niches, and the organization and localization of tertiary lymphoid structures. We also examine how fibroblast heterogeneity, collagen architecture, hyaluronan accumulation, and vascular dysfunction can restrict T-cell access and function. Emerging studies associate selected spatial features with treatment outcomes, but the supporting evidence spans small treatment-specific cohorts, mixed CRC populations, and preclinical or non-CRC models. These findings therefore support spatial profiling as a complement to molecular and clinical biomarkers rather than an independently established basis for treatment selection. Prospective studies in defined treatment settings are needed to clarify the relationship between these spatial features and immunotherapy outcomes and to assess their potential to inform combination strategies in MSS CRC.