IGF2BP1 的变构调节作为激活肿瘤免疫微环境的新策略

Tumor immune microenvironment (TIME) regulators are promising cancer immunotherapeutic targets. IGF2BP1, as a crucial N 6 -methyladenosine (m 6 A) reader protein, recognizes m 6 A 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 m 6 A 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.