Li Chenghui, Xing Xiao, Li Mingzhi, Liu Yonglei, Huang Sinian, Zhu Ting, Gu Wei, Yan Bin
Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201799, China.
Medical Research Center Laboratory, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201799, China.
Int Immunopharmacol. 2025 Jun 17;158:114829. doi: 10.1016/j.intimp.2025.114829. Epub 2025 May 13.
CRLM (Colorectal liver metastasis), a prevalent form of distant metastasis in colorectal cancer, is a leading cause of mortality in affected patients. Despite advancements in immunotherapy for colorectal cancer, clinical benefits in CRLM patients remain limited. The immunosuppressive liver microenvironment plays a pivotal role in facilitating metastatic colonization and disease progression.
We performed fecal metabolomics in ABX (antibiotic-treated) mice and single-cell RNA sequencing on hepatic tissues from four cohorts: CRC (colorectal cancer) , CRLM, LCA-fed CRC, and LCA-fed CRLM mice, to delineate intergroup immune heterogeneity. Cellular and molecular profiling across groups was conducted via Luminex multiplex assays, flow cytometry, and immunofluorescence. Integrated multi-omics analyses elucidated LCA-driven pathways modulating metastatic progression RESULTS: We demonstrated that LCA (lithocholic acid), a gut microbiota-derived metabolite, activates TGR5 in hepatic CAFs (cancer-associated fibroblasts) to upregulate CCL3 secretion. Elevated CCL3 levels subsequently recruit MDSCs (myeloid-derived suppressor cells) into metastatic niches. While MDSCs primarily suppress T-cell activation, we identified a paradoxical role of MDSC-derived CCL2 in attenuating immunosuppression via CCR2 signaling, suggesting a compensatory pro-inflammatory axis within the tumor microenvironment CONCLUSIONS: These findings suggest new immunotherapeutic strategies for the treatment of CRLM.
结直肠癌肝转移（CRLM）是结直肠癌远处转移的一种常见形式，是影响患者死亡的主要原因。尽管结直肠癌免疫治疗取得了进展，但CRLM患者的临床获益仍然有限。免疫抑制性肝微环境在促进转移定植和疾病进展中起关键作用。
我们对ABX（抗生素处理）小鼠进行了粪便代谢组学分析，并对四个队列（结直肠癌（CRC）、CRLM、LCA喂养的CRC和LCA喂养的CRLM小鼠）的肝组织进行了单细胞RNA测序，以描绘组间免疫异质性。通过Luminex多重分析、流式细胞术和免疫荧光对各组进行细胞和分子分析。综合多组学分析阐明了LCA驱动的调节转移进展的途径。
我们证明，肠道微生物群衍生的代谢产物石胆酸（LCA）激活肝癌症相关成纤维细胞（CAF）中的TGR5，上调CCL3分泌。升高的CCL3水平随后将骨髓来源的抑制细胞（MDSC）募集到转移龛中。虽然MDSC主要抑制T细胞活化，但我们发现MDSC衍生的CCL2通过CCR2信号传导在减轻免疫抑制方面具有矛盾的作用，这表明肿瘤微环境中存在补偿性促炎轴。
这些发现为CRLM的治疗提出了新的免疫治疗策略。
