Cancer-associated fibroblasts as architects of acquired immune-privileged-like niches in gastrointestinal cancers: lessons from ocular immune privilege and barrier biology

Abstract

Gastrointestinal cancers frequently develop immune exclusion and therapeutic resistance, yet these phenotypes are often described separately. Cancer-associated fibroblasts (CAFs) are key stromal architects of immune-excluded tumor microenvironments, and their heterogeneous states can evolve under chemotherapy, radiotherapy, immunotherapy, targeted therapy, and anti-angiogenic pressure. We propose that treatment-induced injury, inflammation, hypoxia, and repair signals reshape CAFs. These therapy-educated CAFs can construct acquired immune-privileged-like niches by integrating extracellular matrix remodeling, immunosuppressive secretomes, vascular-barrier remodeling, and spatial exclusion of cytotoxic immune cells. Ocular barrier biology offers a conceptual, not anatomical, analog for this spatial organization. In gastrointestinal tumors, these principles may be pathologically co-opted by myCAF-, iCAF-, and apCAF-like programs to restrict CD8+ T-cell and NK-cell access, recruit suppressive myeloid and regulatory populations, and impair drug delivery. This framework may guide spatial multiomics, digital pathology, radiomics, CAF-derived biomarkers, and spatially guided CAF reprogramming strategies. It also provides falsifiable questions for paired pre- and post-treatment sampling across gastrointestinal cancer types.