Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs
Qing Liao, … , Yanqing Ding, Liang Zhao
Qing Liao, … , Yanqing Ding, Liang Zhao
Published April 3, 2025
Citation Information: J Clin Invest. 2025;135(11):e181243. https://doi.org/10.1172/JCI181243.
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Research Article Gastroenterology Immunology Oncology

Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs

Abstract

Colorectal cancer (CRC) is characterized by an immune-suppressive microenvironment that contributes to tumor progression and immunotherapy resistance. The gut microbiome produces diverse metabolites that feature unique mechanisms of interaction with host targets, yet the role of many metabolites in CRC remains poorly understood. In this study, the microbial metabolite 4-hydroxybenzeneacetic acid (4-HPA) promoted the infiltration of PMN myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment, consequently inhibiting the antitumor response of CD8+ T cells and promoting CRC progression in vivo. Mechanistically, 4-HPA activates the JAK2/STAT3 pathway, which upregulates CXCL3 transcription, thereby recruiting PMN-MDSCs to the CRC microenvironment. Selective knockdown of CXCL3 resensitized tumors to anti-PD-1 immunotherapy in vivo. Chlorogenic acid reduces the production of 4-HPA by microbiota, likewise abolishing 4-HPA–mediated immunosuppression. The 4-HPA content in CRC tissues was notably increased in patients with advanced CRC. Overall, the gut microbiome uses 4-HPA as a messenger to control chemokine-dependent accumulation of PMN-MDSC cells and regulate antitumor immunity in CRC. Our findings provide a scientific basis for establishing clinical intervention strategies to reverse the tumor immune microenvironment and improve the efficacy of immunotherapy by reducing the interaction among intestinal microbiota, tumor cells, and tumor immune cells.

Authors

Qing Liao, Ximing Zhou, Ling Wu, Yuyi Yang, Xiaohui Zhu, Hangyu Liao, Yujie Zhang, Weidong Lian, Feifei Zhang, Hui Wang, Yanqing Ding, Liang Zhao

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Figure 2

F. nucleatum and E. coli mediate immunosuppressive microenvironment in CRC.

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F. nucleatum and E. coli mediate immunosuppressive microenvironment in ...
(A) Schematic diagram of the microbiota-treated Apcmin/+ tumorigenesis mouse model administration method (n = 5). (B) Colonization efficiency of E. coli and F. nucleatum was assessed by metagenomic sequencing analysis of Apcmin/+ mice after 8 days (5 days of antibiotics treatment to deplete their gut microbiota, followed by 3 days of F. nucleatum, E. coli, or PBS orally administration for microbiota colonization) . The relative abundance of Operational Taxonomic Units (OTUs) in fecal bacterial is shown. (C) Representative images of tumors in the intestines of Apcmin/+ mice are shown. (D) Statistics of tumor load of the intestines derived from Apcmin/+ mice treated with PBS, E. coli, or F. nucleatum (n = 5). (E) Representative images of tumorigenesis of intestines in Apcmin/+ mice visualized by H&E staining. (F) H&E scoring of tumor-related lesions (including inflammation, adenoma, atypical hyperplasia, and crypt fusion) (n =5). (G) The percentages of PMN-MDSCs (CD11b+Ly6G+Ly6Clow) and M-MDSCs (CD11b+Ly6G-Ly6Chi) in TILs (CD45+) of Apcmin/+ mice were determined by flow cytometry sorting. (H and I) Statistical chart of PMN-MDSCs and M-MDSCs (n = 5). (J) The percentage of Tregs (CD4+Foxp3+) in TILs (CD45+) of Apcmin/+ mice, detected by flow cytometry sorting. (K) Statistical chart of Tregs (n = 5). (L) Tumor-infiltrating CD8+T cells in TILs (CD45+) of Apcmin/+ mice, detected by flow cytometry sorting. (M). Statistical chart of CD8+T cells (n = 5). (N) The granule productions (GzmB+) of CD8+T cells. (O) Statistical chart of GzmB+ cells (n = 5). Data and error bars represent the mean ± SD of 3 independent experiments. Statistical analyses were conducted using 1-way ANOVA with Dunnett’s T3 correct multiple-comparison test. *P < 0.05, **P < 0.005, ***P < 0.0005.