Koumine alters immune barrier function by targeting TGFβ-mediated collagen deposition in gastric cancer.

Gastric cancer (GC) is one among the most fatal cancers worldwide. Although immunotherapy has expanded the treatment options for patients with advanced GC, the immunosuppressive tumor microenvironment (TME) of GC renders it resistant to immunotherapy. This underscores the urgent need for strategies to enhance the efficacy of immunotherapies. In this study, we identified a natural compound Koumine, which suppresses GC cancer growth in vivo, however, not in vitro. Koumine markedly reduced collagen (COL21A1, COL3A1, COL13A1, and COL14A1) expression in GC cells and significantly increased T-cell infiltration into the tumors. Mechanistically, Koumine was observed to directly bind to and inhibit the kinase activity of transforming growth factor beta receptor 1 (TGFβR1), thereby suppressing Smad2/3 signaling, which led to the downregulation of collagen proteins and increased anti-tumor immunity. Furthermore, the combination of Koumine with anti-PD1 immune checkpoint inhibitor generated synergistic effects in immune-competent GC mouse models, enhancing CD8 T-cell infiltration and significantly inhibiting tumor growth. The results of our study suggest that Koumine is a potent agent that may be used to disrupt immune exclusion and optimize immunotherapy in patients with GC.