Resident mucosal programmes in colon cancer: organ-associated formation and remodelling of the immune niche

Resident epithelial, immune and stromal cells organise immune responses in the colonic mucosa, but their contribution to the immune environment of colon cancer remains incompletely understood. We propose that colonic tumours may partly use pre-existing mucosal cells and regulatory mechanisms, a possibility we refer to as co-option. Chronic colitis provides a comparison for examining changes in mucosal immunity, without implying that inflammation is a necessary precursor to sporadic colon cancer. Colonic BTNL3/BTNL8 proteins regulate resident γδ T-cell subsets, and compartmentalised antigen presentation shapes local immune responses. In mouse models of colitis-associated cancer, resident stromal cells give rise to MCAM + cancer-associated fibroblasts that promote macrophage recruitment through IL-34/CCL8 signalling. Tumour-associated immune changes include shifts in γδ T-cell subset composition and altered functions of RORγt + regulatory T cells. MHC class II-dependent interactions between group 3 innate lymphoid cells and T cells also support microbiota-dependent antitumour immunity. Shared signalling is exemplified by the IL-22–oncostatin M–STAT3 pathway in experimental colitis and colitis-associated cancer. However, similarity in cell states and signalling does not establish that tumours preserve pre-existing multicellular mucosal niches. Much of the causal evidence derives from colitis-associated cancer models, and its relevance to sporadic colon cancer remains uncertain. Whether tumours use the same mucosal cells and regulatory mechanisms requires direct testing. Defining tumour-associated changes in these mechanisms may reveal therapeutic targets while preserving protective intestinal immunity.