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World J Gastroenterol. Jul 21, 2026; 32(27): 118794
Published online Jul 21, 2026. doi: 10.3748/wjg.118794
Gram-negative bacteria and endotoxins promote hepatocellular carcinoma progression through the recruitment of myeloid-derived suppressor cells
Yong Zhang, You-Lian Zhou, Xin Nie, Liang-Jie Zhang, Wei-Wei Xu, Jia-Qi Wang, Hai-Lan Zhao, Jing-Kui Xu, Jing Xu, Hao-Ming Xu, Jian-Hong Li, Wen-Qi Huang, Jing Yang, Yao-Xiang Yang, Qi Zhan, Yong Lin, Yu-Qiang Nie
Yong Zhang, You-Lian Zhou, Xin Nie, Wei-Wei Xu, Jia-Qi Wang, Hai-Lan Zhao, Jing-Kui Xu, Jing Xu, Hao-Ming Xu, Jian-Hong Li, Wen-Qi Huang, Yong Lin, Yu-Qiang Nie, Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou 510180, Guangdong Province, China
Yong Zhang, Department of Gynecology, Yichang Central People’s Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang 443000, Hubei Province, China
Liang-Jie Zhang, Department of Infection Division, The First Affiliated Hospital of Bengbu Medical University, Bengbu 223000, Anhui Province, China
Jing Yang, Yao-Xiang Yang, Department of Pathology, The Second Affiliated Hospital, School of Medicine, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou 510180, Guangdong Province, China
Qi Zhan, Department of Infectious Diseases, The Second Affiliated Hospital, School of Medicine, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou 510180, Guangdong Province, China
Co-first authors: Yong Zhang and You-Lian Zhou.
Co-corresponding authors: Yong Lin and Yu-Qiang Nie.
Author contributions: Zhang Y and Zhou YL contributed equally to this article and they are the co-first authors of this study; Zhang Y wrote original draft, performed formal analysis, and validations; Zhou YL, Zhan Q, Lin Y and Nie X edited the original draft; Zhang LJ and Xu JK were responsible for patient selection and consent; Wang JQ was responsible for cases classification; Zhang Y, Xu WW, Zhao HL, Xu J, Xu HM, Li JH and Huang WQ performed the laboratory experiments, analyzed the data and interpreted the results; Nie X, Yang J, Yang YX designed the methods; Zhou YL, Lin Y and Nie YQ supervised, conceptualized and administrated the project; Lin Y and Nie YQ reviewed original draft and they contribute equally to this study as co-corresponding authors; all authors have agreed on the journal to which the article has been submitted and agree to be accountable for all aspects of the work.
Supported by National Natural Science Foundation of China, No. 82203371; Natural Science Foundation of Guangdong Province, No. 2022A1515010392; Yu-Qiang Nie Key Laboratory of Digestive Diseases in 2022, No. KY17010003; and Doctoral Research Start-up Fund of Yichang Central People’s Hospital (2024).
Institutional review board statement: All experimental procedures were approved by the Clinical Research Ethics Committee of the Second Affiliated Hospital of South China University of Technology (Approval No. K-2022-031-02).
Institutional animal care and use committee statement: All experimental procedures were approved by the Animal Ethics Committee of The Second Affiliated Hospital of South China University of Technology (Approval No. K-2023-014-01).
Conflict-of-interest statement: The authors declare that they have no competing interests.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data that support this study are available from the corresponding author upon reasonable request.
Corresponding author: Yu-Qiang Nie, MD, Dean, Professor, Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, Guangzhou First People’s Hospital, South China University of Technology, No. 1 Panfu Road, Yuexiu District, Guangzhou 510180, Guangdong Province, China.
eynieyuqiang@scut.edu.cn
Received: January 14, 2026
Revised: February 22, 2026
Accepted: March 10, 2026
Published online: July 21, 2026
Processing time: 174 Days and 3.5 Hours
BACKGROUND
Bacteria were detected in several human malignancies; however, their presence and biological significance in hepatocellular carcinoma (HCC) remain incompletely characterized.
AIM
To investigate the role of bacterial components in HCC and to elucidate their effects on the tumor.
METHODS
Different experimental techniques have proved the presence of bacteria in HCC. Based on lipopolysaccharide (LPS) staining intensity, patients were stratified into LPSlow and LPShigh groups, and overall survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards models. Associations among TLR4, CCL2, CCR2, and myeloid-derived suppressor cells (MDSCs) were explored using transcriptomic data from The Cancer Genome Atlas cohort. Functional experiments included LPS and lipoteichoic acid stimulation or inhibition in HCC cell lines and animal models, as well as transcriptome sequencing to identify differentially expressed genes and enriched signaling pathways.
RESULTS
LPS positive signals were detected in a significant proportion of 93 HCC pathological specimens. Compared with matched controls, fresh HCC tissues exhibited a significantly increased bacterial load. Patients in the LPShigh group demonstrated a significantly poorer prognosis, accompanied by elevated CD33 expression level and reduced CD8 expression level. Functional inhibition of TLR4 in HCC models revealed that LPS promoted the accumulation of monocytic MDSCs (MMDSCs) in the tumor microenvironment. In addition, neomycin treatment in HCC models reshaped both intestinal and intratumoral microbial composition, reduced MMDSC accumulation, and suppressed tumor growth.
CONCLUSION
Bacterial components, particularly LPS, play a significant role in HCC progression by modulating immune responses. Targeting the TLR4-CCL2-CCR2-MDSCs axis may provide a novel therapeutic approach for HCC.
Core Tip: The presence of intratumoral bacteria was identified in a subset of hepatocellular carcinoma (HCC) cases. Gram-negative bacteria and their associated endotoxins were found to promote the recruitment of monocytic myeloid-derived suppressor cells through activation of the TLR4/CCL2/CCR2 signaling axis. This process may contribute to the establishment of an immunosuppressive tumor microenvironment, thereby influencing both tumor progression and clinical prognosis in HCC. Collectively, our findings identified lipopolysaccharide (LPS) as a potential prognostic biomarker for HCC and indicated that therapeutic targeting of the LPS/TLR4/CCL2/CCR2/monocytic myeloid-derived suppressor cell axis may represent a promising strategy for future HCC treatment.
