KRAS基因突变促进肠上皮细胞异常增生并抑制肠道免疫微环境是结直肠癌（Colorectal Cancer, CRC）复发和难治的重要原因。转化生长因子-β激活激酶1（TAK1）是KRAS突变CRC生存依赖的激酶。我们在小鼠原位结肠癌研究中发现，TAK1抑制剂特异性诱导KRAS突变细胞凋亡，并与免疫反应正相关；抑制TAK1可使体外混合培养体系中CD8+T数量增多，肿瘤和CD3+细胞表面PD-L1表达下降，提示TAK1可调控KRAS突变CRC免疫微环境。据此提出假设：TAK1抑制剂诱导KRAS突变细胞免疫原性死亡并激活抗肿瘤免疫反应。本课题将阐明TAK1通过调节KRAS突变肿瘤免疫微环境中细胞因子并下调PD-L1表达，逆转KRAS突变相关免疫逃逸的机制。研究结果将验证TAK1具有抑制KRAS突变细胞异常增殖和激活免疫微环境的双重效应，是靶向和免疫联合治疗KRAS突变CRC的潜在靶点。

Mutations in the KRAS oncogene represent one of the most prevalent genetic alterations in colorectal cancer (CRC), the third leading cause of cancer-related death in the world. Besides their well-characterized functions in driving tumor progression, KRAS mutations can induce tumor immunoresistance by increasing the expression of PD-L1 and immunosuppressive cytokines directly or via downstream signal pathways. KRAS mutation has been linked to resistance to the agents utilized in front-line therapy of CRC. KRAS mutation in CRC activates transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1) to promote tumor progression. Our preliminary studies showed that TAK1 inhibitor NG25 induced apoptosis of KRAS mutant CRC cells and the percentage of apoptosis were positively correlated with host immunity in orthotopic CRC mouse models. The number of CD3+CD8 + T cells was increased as well as PD-L1 expression was decreased in both CT26 (KRAS mutant CRC cells) and CD3+ cells, which were treated with NG25 in the mixed culture system. Based on above, we hypothesize that inhibition of TAK1 could induce KRAS mutant cells immunogenic death and enhance antitumor immune responses in colorectal cancer. Our project is going to clarify that the apoptosis induced by TAK1 inhibitor is immunogenic; TAK1 can modulate immune related-cytokines to recruit immune cells and/or induce their differentiation, and downregulate PD-L1 expression, then produce a therapeutically effective anti-KRAS mutant CRC response. In summary, inhibition of TAK1 could induce apoptosis in KRAS mutant cells and activate anti-tumor immunity simultaneously in CRC microenvironment. It may serve as a novel biomarker and potential therapeutic target in KRAS mutant CRC.