The Role of IGF2BP3-Mediated Immune Response Activation in Enhancing Immunotherapy of Koumine for Gastric Cancer

Gastric cancer (GC) remains a lethal malignancy with suboptimal responses to current immunotherapies. The natural alkaloid koumine (KM) has shown immunomodulatory potential, but its precise mechanism in enhancing GC immunotherapy remains unclear. This study aimed to elucidate the molecular mechanism by which KM augments anti-tumor immunity and synergizes with immune checkpoint blockade in GC. Network pharmacology, proteomics, surface plasmon resonance, and cellular thermal shift assays were used to identify and validate KM’s target. Genetic rescue experiments, in vitro T cell co-culture assays, and in vivo GC mouse models were performed to establish functional causality. m6A-seq and ChIP-seq analyses delineated the downstream epigenetic pathway. KM directly bound to and degraded the RNA-binding protein IGF2BP3, triggering m6A-dependent suppression of H3K27 trimethylation to relieve epigenetic repression of MHC-I genes. This resulted in upregulation of MHC-I expression in GC cells, enhancing their recognition and elimination of CD8⁺ T cells. Overexpression of IGF2BP3 could abolish KM-induced MHC-I restoration and T cell-mediated cytotoxicity. Crucially, KM synergized with anti-PD-1 therapy in GC mouse models, suppressing tumor growth and fostering an immunologically active tumor microenvironment. Our findings position KM as a promising candidate for further investigation as a tumor immunomodulator and immunotherapy sensitizer for GC.