Ding Tingting, Wu Minkang, Zhao Li, Liu Hu, Cao Xuanke, Guo Jing, Zhu Xingchen, Zhao Lamei, Zhang Heping, Gao Yaohui, Wei Qing
Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Tongji University, Shanghai, China.
Department of Medical Oncology, Jinling Hospital, Affiliated Hospital of Medicine School, Nanjing University, Nanjing, China.
Front Immunol. 2025 May 19;16:1586146. doi: 10.3389/fimmu.2025.1586146. eCollection 2025.
() has been shown to be associated with immunotherapy in colorectal cancer (CRC), but its exact mechanism needs to be further explored.
We first analyzed the correlation between abundance and mismatch repair (MMR) protein deficiency in CRC tissues from 567 patients. We then treated CRC cells and tissues with and its metabolites. RNA sequencing was used to evaluate the involved pathways, and non-targeted metabolomics was employed to analyze the metabolites regulating MLH1. CRC cells were treated with butyrate, a metabolite of , with or without the autophagy-lysosome pathway inhibitor chloroquine or mTOR activator MHY1485. Finally, subcutaneous tumors of BALB/C mice were treated with PD-L1 blockade, butyrate, or their combination.
The results showed that the abundance of in CRC tissues is correlated with MSI and MLH1 deficiency. , its culture supernatant, and its metabolite butyrate cause the downregulation of MLH1 protein via autophagy-lysosome pathway. Subcutaneous tumors in mice received the combined treatment of PD-L1 blockade and butyrate shrink more evidently than those disposed by single therapy.
reduces MLH1 expression via the lysosomal pathway by butyrate, leading to deficient mismatch repair (dMMR), which may yield therapeutic benefits in CRC patients with microsatellite stability (MSS).
（）已被证明与结直肠癌（CRC）的免疫治疗相关，但其确切机制有待进一步探索。
我们首先分析了567例CRC患者肿瘤组织中（）丰度与错配修复（MMR）蛋白缺陷之间的相关性。然后用（）及其代谢产物处理CRC细胞和组织。采用RNA测序评估相关通路，并用非靶向代谢组学分析调节MLH1的代谢产物。用（）的代谢产物丁酸盐处理CRC细胞，同时或不同时使用自噬 - 溶酶体途径抑制剂氯喹或mTOR激活剂MHY1485。最后，用PD - L1阻断剂、丁酸盐或其组合处理BALB/C小鼠的皮下肿瘤。
结果表明，CRC组织中（）的丰度与微卫星高度不稳定（MSI）和MLH1缺陷相关。（）及其培养上清液和代谢产物丁酸盐通过自噬 - 溶酶体途径导致MLH1蛋白下调。接受PD - L1阻断剂和丁酸盐联合治疗的小鼠皮下肿瘤比单一治疗的肿瘤缩小更明显。
（）通过丁酸盐经由溶酶体途径降低MLH1表达，导致错配修复缺陷（dMMR），这可能对微卫星稳定（MSS）的CRC患者产生治疗益处。
