Wumei Wan Remodels the Tumor Immune Microenvironment via the IDO1-KYN-AHR Axis in AOM/DSS-Induced Colorectal Cancer Model.
Abstract Background:Colorectal Cancer (CRC) is a common malignant tumor of the digestive tract, with poor prognosis in advanced stages due to metastasis and immune evasion.Chronic intestinal inflammation may promote CRC progression by inducing an imbalance in the immune microenvironment, thus therapeutic strategies targeting immune regulation urgently need to be explored.Wumei Wan (WMW), a traditional Chinese herbal formula, has shown marked anti-inflammatory activity in ulcerative colitis (UC).However, whether it can inhibit CRC progression remains unclear. Aim:This study aims to investigate whether WMW can ameliorate CRC and to explore its underlying mechanisms. Methods:An AOM/DSS-induced CRC mouse model was established, and transcriptomicss, metabolomics, and network pharmacology analyses were integrated to investigate and validate the mechanisms of WMW. Results:WMW ameliorated CRC progression by improving colonic pathological conditions, lowering Disease Activity Index (DAI) scores, enhancing survival, and suppressing tumor growth in CRC mice. Specifically, the WMW group's DAI score decreased by approximately 34.36% compared to the model group. Additionally, by day 70, the survival rate in the WMW-treated group was 22.806% higher than that of the model group. Multi-omics and network pharmacology analyses indicated that WMW inhibited the IDO-Kyn-AHR signaling pathway, decreased Th17 and Treg cell proliferation and differentiation, restored CD8+T cell function, and enhanced antitumor immunity. Conclusion:This research demonstrates for the first time that WMW suppresses CRC progression by rebalancing Th17/Treg immunity through modulation of the IDO1-Kyn-AHR pathway. Overall design: The RNA-seq analysis of mouse colorectal cancer tissues includes three experimental groups: the blank control group (Group K), the colorectal cancer model group (Group M), and the WMW-H treatment group (Group G), with 5 replicates in each group, to observe the therapeutic effect of WMW-H.