Modulating the gut microbiota to enhance immune checkpoint inhibitor efficacy in colorectal cancer: mechanisms, therapeutic strategies, and clinical perspectives.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their efficacy in colorectal cancer (CRC) remains limited to a minority of patients with microsatellite instability-high (MSI-H) tumors, leaving the majority with microsatellite stable (MSS) disease unresponsive. The gut microbiota, a key regulator of host immunity, has emerged as a pivotal determinant of ICI response. This review delineates the dual role of the gut microbiome-encompassing specific bacterial strains, their metabolites, and bioactive components such as extracellular vesicles (EVs) and outer membrane vesicles (OMVs)-in either enhancing or impairing ICI efficacy through complex interactions with the host immune system. We further explore the emerging concept of gut microbiota circadian rhythms and their potential to inform personalized chrono-immunotherapy paradigms. Furthermore, we synthesize promising microbiota-targeting strategies as adjunctive approaches to overcome resistance and augment ICI efficacy in CRC. Finally, we present selected clinical evidence and outline future perspectives to expand the clinical benefit of immunotherapy in CRC patients.