CD47 fuels intestinal fibrosis by inducing fibroblast phagocytic evasion and represents a therapeutic target.

Intestinal fibrosis is a major complication of Crohn's disease, for which targeted therapies remain unavailable. Fibrosis is defined by excess matrix deposition, which may result from inadequate phagocytic clearance, yet how phagocytosis shifts here is unclear. Using single-cell and spatial transcriptomics, we identify fibrosis-associated CD47hi fibroblasts coupled to SIRPAhi macrophages in fibrotic regions. Cell-cell communication analyses and neutralizing-antibody experiments identify interleukin-1β as a mediator of their crosstalk, forming a profibrotic niche characterized by phagocytic evasion. Genetic disruption of fibroblast Cd47 or macrophage Sirpa enhances fibroblast clearance and attenuates fibrosis. Mechanistically, checkpoint disruption reprograms macrophages toward an NRF2-associated pro-phagocytic state, linking enhanced clearance to the antifibrotic response. Furthermore, therapeutic antibody blockade of this checkpoint attenuates intestinal fibrosis in mouse models with schedule-dependent efficacy. Collectively, these findings support CD47-mediated phagocytic evasion as a key pathogenic mechanism in intestinal fibrosis and identify CD47-SIRPα blockade as a promising therapeutic target.