Supplementation with Akkermansia muciniphila Enhances the αPD-1 Efficacy in Mice Transplanted with Gut Microbiota from Patients with Colorectal Cancer.

INTRODUCTION

The resistance of colorectal cancer (CRC) to PD-1 blockade has positioned it as a critical focus of global research efforts. The gut microbiota is a key regulator of anti-tumor immunity, but research on bacteria that are clearly associated with primary resistance to PD-1 blockade in colorectal cancer remains incomplete.

METHODS

In this study, C57BL/6 mice were subjected to antibiotic pretreatment to deplete endogenous gut microbiota. The mice were then gavaged with fecal suspensions from treatment-naïve CRC patients or healthy donors, subsequently implanted with MC38 tumor cells to establish the tumor model, and then treated with the drug. Gut microbial composition was analyzed by 16S rRNA sequencing, while tumor-infiltrating immune cells and cytokine profiles were characterized using flow cytometry and immunohistochemistry, respectively.

RESULTS

CRC patient microbiota conferred resistance to anti-PD-1 therapy in mice, an effect completely reversed by oral Akkermansia muciniphila (Akk). Mechanistically, Akk reconfigured the tumor immune microenvironment, leading to a substantial increase in CD8+ T cell infiltration and function. Crucially, this potent local anti-tumor immunity was achieved without systemic immune activation.

DISCUSSION: In summary, this study establishes that Akk amplifies the local CD8⁺ T cell response, sensitizing tumors to anti-PD-1 therapy, without inducing a systemic inflammatory response.

CONCLUSION

These findings position Akk supplementation as a promising, targeted strategy to overcome PD-1 immunotherapy resistance of MSS-CRC with a favorable safety profile.