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

ABSTRACT Resistance to immune checkpoint blockade in gastric cancer often arises from defective antigen presentation due to MHC‐I downregulation, yet strategies to restore MHC‐I expression remain limited. Here, using the natural alkaloid koumine as a chemical probe, we identified IGF2BP3 as a druggable regulator of MHC‐I antigen presentation. Network pharmacology, proteomics, surface plasmon resonance, and cellular thermal shift assays were used to identify and validate koumine's target. Genetic rescue experiments, loss‐of‐function studies, in vitro T‐cell co‐culture assays, and in vivo gastric cancer mouse models were performed to confirm the causal relationship. m6A‐seq and ChIP‐seq analyses delineated the downstream epigenetic pathway. Koumine binds IGF2BP3 and promotes its proteasome‐dependent degradation, which reduces m6A enrichment on EED mRNA, accelerates EED decay, lowers H3K27me3, and derepresses IRF transcription, thereby restoring MHC‐I expression and enhancing CD8 + T‐cell killing. Crucially, koumine enhanced the efficacy of anti‐PD‐1 therapy in gastric cancer mouse models, suppressing tumor growth and fostering an immunologically active tumor microenvironment characterized by CD8 + T‐cell infiltration and activation. This study identifies IGF2BP3 as an actionable target for improving antigen presentation and establishes koumine as a valuable chemical probe to dissect this pathway, with implications for immunotherapy sensitization beyond gastric cancer.