KIAA1429介导STING的m6A甲基化修饰促进结肠癌恶性进展及免疫逃逸的机制研究

结肠癌仍是发病率及死亡率较高的肿瘤。目前已发现N6-甲基腺嘌呤（m6A）修饰在调节肿瘤恶性表型及免疫应答过程中发挥重要作用。本课题将聚焦探索结肠癌中m6A甲基转移酶KIAA1429在肿瘤进展及免疫逃逸的作用机制。预实验发现KIAA1429高表达促进结肠癌增殖、侵袭能力并潜在调控STING通路的激活。接下来将运用多种实验手段阐明KIAA1429通过靶向STING pre-mRNA的m6A甲基化修饰及表达，阻碍STING-TBK1-IRF3激活，抑制I型IFN、炎症细胞因子等的分泌和BAX诱导的细胞凋亡，促进肿瘤免疫逃逸和恶性表型的产生。靶向沉默KIAA1429可以打破机体免疫抑制状态，并可联合PD-1抗体协同增强抗肿瘤免疫应答效果。本研究设计基于前期详实的实验结果和理论指导，有望为揭示结肠癌免疫应答新机制、靶向新药的研发提供实验基础，有助于推动结肠癌患者的精准免疫治疗和临床获益。

Colon cancer remains a malignant tumor with high morbidity and mortality rate. It has been recognized that N6-methyladenosine (m6A) modification plays an important role in regulating tumor malignant phenotype and immune response. This study will focus on exploring the molecular mechanism of m6A methyltransferase KIAA1429 on tumor progression and immune evasion in colon cancer. Preliminary experiments have identified that KIAA1429 promoted colon cancer proliferation, invasion and potentially mediated STING signaling activation. Furthermore, we will use multiple experimental technologies to identify that KIAA1429 targets the m6A modification of STING pre-mRNA and downregulates the expression of STING, thus blocking the STING-TBK1-IRF3 pathway activation, inhibiting the IFN-I, inflamed-related molecule expression and Bax induced apoptosis, and leading to tumor progression and immune evasion. This project design is based on substantial experiment and theoretical basis, and provides important foundation for revelation of novel immune response mechanism and development of targeted new drug in colon cancer, which will facilitate personalized immune precision therapy and maximize the survival benefit of patients.