Tumor immune microenvironment (TIME) regulators are promising cancer immunotherapeutic targets. IGF2BP1, as a crucial N6-methyladenosine (m6A) reader protein, recognizes m6A target transcripts, ultimately leading to cancer development. However, currently, the… Click to show full abstract
Tumor immune microenvironment (TIME) regulators are promising cancer immunotherapeutic targets. IGF2BP1, as a crucial N6-methyladenosine (m6A) reader protein, recognizes m6A target transcripts, ultimately leading to cancer development. However, currently, the biological function of IGF2BP1 in regulating the TIME is not well-understood. In this study, we report that IGF2BP1 knockdown induces cancer cell apoptosis, thereby significantly not only activating immune cell infiltration including CD4+, CD8+ T cells, CD56+ NK cells, and F4/80+ macrophage but also decreasing PD-L1 expression in hepatocellular carcinoma (HCC). Then, chemical genetics identifies a small-molecule cucurbitacin B (CuB), which directly targets IGF2BP1 at a unique site (Cys253) in the KH1–2 domains. This leads to a pharmacological allosteric effect to block IGF2BP1 recognition of m6A mRNA targets such as c-MYC, which is highly associated with cell apoptosis and immune response. In vivo, CuB exhibits an obvious anti-HCC effect through inducing apoptosis and subsequently recruits immune cells to tumor microenvironment as well as blocking PD-L1 expression. Collectively, IGF2BP1 may serve as a novel pharmacological allosteric target for anticancer therapeutics via mediating TIME.
               
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