Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences, People's Hospital of Sichuan Provincial, Chengdu, 610101, Sichuan Province, China.
Apoptosis. 2024 Dec;29(11-12):2147-2160. doi: 10.1007/s10495-024-02020-w. Epub 2024 Oct 13.
The CD8 T cells mediated antitumor immunity plays a critical function on gastric cancer (GC) immunotherapy. However, the mechanism of N-methyladenosine (mA) and lactate in GC immune microenvironment are still unclear. Here, present research investigated the role of Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) in GC and its in-depth mechanisms in the antitumor immunity. Data illustrated that high IGF2BP3 level was associated to GC poor prognosis and tumor infiltration. Functional assays demonstrated that IGF2BP3 overexpression could promote the lactate accumulation, and impair the CD8 T cells' antitumor immunity activity in co-culture system. Correspondingly, IGF2BP3 silencing enhanced the CD8 T cells' antitumor immunity activity towards co-cultured GC cells. Mechanistically, IGF2BP3 could bind the mA site on LDHA mRNA, thereby promoting its mRNA stability. Rescue assays elucidated that IGF2BP3/LDHA axis impaired the CD8 T cells antitumor immunity by triggering lactate excess tumor microenvironment. In conclusion, our findings demonstrate that IGF2BP3 impairs the CD8 T cells antitumor immunity by targeting LDHA/lactate axis, providing a novel therapeutic insight for GC immunotherapy.
CD8 T 细胞介导的抗肿瘤免疫在胃癌（GC）免疫治疗中起着关键作用。然而，N-甲基腺苷（m6A）和乳酸在 GC 免疫微环境中的作用机制尚不清楚。本研究探讨了胰岛素样生长因子 II mRNA 结合蛋白 3（IGF2BP3）在 GC 中的作用及其在抗肿瘤免疫中的深入机制。数据表明，IGF2BP3 水平高与 GC 预后不良和肿瘤浸润有关。功能分析表明，IGF2BP3 过表达可促进乳酸积累，并在共培养系统中损害 CD8 T 细胞的抗肿瘤免疫活性。相应地，IGF2BP3 沉默增强了 CD8 T 细胞对共培养 GC 细胞的抗肿瘤免疫活性。在机制上，IGF2BP3 可以结合 LDHA mRNA 上的 mA 位点，从而促进其 mRNA 稳定性。挽救实验表明，IGF2BP3/LDHA 轴通过触发乳酸过多的肿瘤微环境来损害 CD8 T 细胞的抗肿瘤免疫。总之，我们的研究结果表明，IGF2BP3 通过靶向 LDHA/乳酸轴损害 CD8 T 细胞的抗肿瘤免疫，为 GC 免疫治疗提供了新的治疗思路。
