Spatial immune archetypes in gastric and colorectal cancer: a proposed conceptual framework for immunotherapy resistance and therapeutic remodeling.

Gastric and colorectal cancers are leading causes of global cancer mortality, yet the transformative benefits of immune checkpoint blockade remain largely confined to the small fraction of patients with MSI-H/dMMR tumors. The vast majority-those with MSS/pMMR disease-exhibit primary resistance, underscoring an urgent need to look beyond bulk immune infiltration and dissect the in situ spatial determinants of immune evasion. We propose that immunotherapy outcome in these malignancies is dictated not by lymphocyte abundance alone, but by highly coordinated multicellular architectures-termed spatial immune archetypes-that govern immune exclusion, metabolic suppression, local activation, and epithelial-immune contact. Enabled by spatial transcriptomics, multiplexed proteomics, and multimodal computational integration, this review proposes a conceptual framework of four spatial archetypes synthesized from existing evidence across gastric and colorectal cancers: (i) the stromal-excluded barrier niche, characterized by CAF-mediated physical sequestration; (ii) the myeloid-suppressive metabolic niche, driven by TREM2+/SPP1TREM2+ macrophages and microbial crosstalk; (iii) the inflamed lymphoid-reactive niche, marked by mature tertiary lymphoid structures; and (iv) the epithelial-immune interface niche, a fragile surveillance equilibrium lost during immunoediting. We further examine how tissue-specific anatomical constraints and distinct microbial ecologies (H. pylori in the stomach, F. nucleatum in the colon) shape the prevalence of each archetype. By elucidating the molecular circuits and environmental dependencies underlying these spatially encoded resistance programs, we articulate a translational imperative: archetype-guided spatial biomarkers and targeted microenvironment-remodeling strategies provide the most viable framework to extend durable immunotherapeutic benefit to the historically refractory MSS/pMMR gastrointestinal cancer population.