Pathological reprogramming of innate immune cells drives resistance to biologics in inflammatory bowel diseases.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic immune-mediated disorder characterized by persist ent intestinal inflammation. With a rising global incidence, IBD poses a significant therapeutic challenge. Although biologic agents targeting TNF, α4β7 integrin, or IL-12/ 23 p40 have improved clinical outcomes, over 40% of patients experience primary non-response or secondary loss of response within the first year, often accompanied by adverse events. This review systematically investigates the dynamic reprogramming of intestinal innate immune cells (particularly macrophages, dendritic cells, and neutr ophils,as well as emerging populations such as eosinophils and ILCs) during biologic therapy and their association with treatment resistance. Under physiological conditions, intestinal innate immune cells maintain barrier integrity, regulate immune tolerance, and facilitate tissue repair. In IBD, however, these cells undergo pathological activation characterized by pro-inflammatory polarization, dysregulated cytokine production, and disrupted interactions with the gut microbiota, thereby sustaining chronic intestinal inflammation. The efficacy of biologic agents in IBD largely relies on their capacity to restrain excessive innate immune activation and rebalance mucosal immune responses. Nevertheless, adaptive reprogramming of these innate immune cells can drive therapeutic resistance through a convergence of mechanisms: sustained activation of inflammatory signaling, metabolic reprogramming that reinforces pro-inflammatory states, induction of pathogenic T cell responses, and self-perpetuating loops that sustain tissue injury. Overall, our findings highlight reprogramming of intestinal innate immune cells as a central mechanism mediating both response and resistance to biologics, offering a mechanistic rationale for future strategies targeting immune cell-microenvironment interactions to overcome therapeutic resistance in IBD.