Single-cell insights into drug response and resistance in inflammatory bowel disease: cellular hallmarks and precision therapy.

BACKGROUND & AIMS: The treatment of inflammatory bowel disease faces a persistent efficacy ceiling, with approximately 30%-50% of patients failing to achieve or sustain remission with current biologics and small-molecule inhibitors. This challenge is partly attributable to profound mucosal heterogeneity. Single-cell and spatial multi-omics technologies have enabled this heterogeneity to be characterized at cellular and spatial resolution. We aimed to synthesize single-cell and spatial multi-omics evidence to clarify the cellular mechanisms underlying therapeutic response and resistance and their implications for precision therapy. METHODS: We examined single-cell evidence across therapies targeting tumor necrosis factor, integrins, interleukin-12/23, and Janus kinases and organized the findings around three interacting cellular hallmarks: immune dysregulation, stromal remodeling, and epithelial reprogramming. RESULTS: Single-cell and spatial multi-omics studies indicate that therapeutic efficacy may depend on the capacity to remodel multicellular communication networks rather than simply neutralizing individual molecular targets. Treatment resistance is associated with bypass pathway activation, drug-induced paradoxical reprogramming and pathogenic subset enrichment, and alternative homing routes. Predictive models link multicellular modules, dynamic gene expression signatures, and multi-omics integration frameworks to treatment outcomes and may facilitate the development of clinically accessible patient-stratification tools. CONCLUSIONS: These findings support a cellular ecosystem framework for understanding therapeutic response and resistance in inflammatory bowel disease. Translating this framework into precision care will require functional validation of candidate mechanisms and prospective clinical evaluation of predictive tools for treatment selection.