Akkermansia muciniphila attenuates macrophage efferocytosis to enhance anti-PD-1 efficacy in microsatellite-stable colorectal cancer.

Approximately 85% of colorectal cancers (CRCs) are microsatellite stable (MSS) and thus exhibit intrinsic resistance to anti-programmed death-1 (PD-1) therapy. In this study, we demonstrate that oral administration of Akkermansia muciniphila (Akk) suppresses tumorigenesis and reprograms the tumor microenvironment in MSS CRC mouse models. Akk attenuates macrophage efferocytosis through the TLR2/NF-κB pathway, an effect that leads to the accumulation of apoptotic cancer cells, which activates the cGAS-STING pathway and potentiates type I interferon production. This immunostimulatory cascade activates effector CD8+ T cells and enhances the response to anti-PD-1 therapy. We conducted a phase 1 trial (NCT06865521) combining Akk probiotics with PD-1 antibody in patients with metastatic MSS CRC after ≥1 prior line of therapy. The combination therapy was safe and achieved an objective response rate of 19%, with responders exhibiting enhanced antitumor immunity. Our multilevel investigation provides a promising strategy to overcome immunotherapy resistance in MSS CRC through targeted modulation of the gut microbiome.