Oral Metformin and Polymetformin Reprogram Immunosuppressive Microenvironment and Boost Immune Checkpoint Inhibitor Therapy in Colorectal Cancer

Abstract

AbstractImmune checkpoint inhibitors (ICI), especially PD‐1/PD‐L1 inhibitors, are emerging as promising therapeutic options for patients with advanced tumors, but the response rate in the majority of colorectal cancer (CRC) patients remains low. Herein, the use of metformin (Met) and its polymeric form (Polymet) to enhance the response rate of immune checkpoint blockade therapy is reported. Oral Met and Polymet significantly enhance the antitumor effect of ICI therapy in a murine orthotopic CRC model. Further analyses reveal that Met and Polymet reprogram the immunosuppressive tumor microenvironment via activation of adenosine 5′‐monophosphate‐activated protein kinase and inhibition of the mammalian target of rapamycin signaling pathway, stimulating T cell infiltration into the tumor. Additionally, oral Met and Polymet change the abundance of key microbes in the intestinal environment, including increasing the Lactobacillus population, which should exert tumor‐suppressing activities in the CRC. These findings highlight the potential of combining Met or Polymet with cancer immunotherapy and provide a strategy for sensitizing CRC patients to immune checkpoint blockade therapy.