2. Academic Validation
  3. Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma

Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma

  • J Exp Med. 2025 Jan 6;222(1):e20241442. doi: 10.1084/jem.20241442.
Jia Ming Nickolas Teo 1,  Zhulin Chen 1,  Weixin Chen 1,  Rachael Julia Yuenyinn Tan 1,  Qi Cao 2 3,  Yingming Chu 2 3,  Delin Ma 4,  Liting Chen 2 3,  Huajian Yu 1,  Ka-Hei Lam 1,  Terence Kin Wah Lee 5 6,  Svetoslav Chakarov 7,  Burkhard Becher 8,  Ning Zhang 2 3,  Zhao Li 4,  Stephanie Ma 1 9 10,  Ruidong Xue 2 3 11 12,  Guang Sheng Ling 1 9 10 13
Affiliations

Affiliations

  • 1 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong, China.
  • 2 Yunnan Baiyao International Medical Research Center, Peking University , Beijing, China.
  • 3 Translational Cancer Research Center, Peking University First Hospital , Beijing, China.
  • 4 Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Beijing, China.
  • 5 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
  • 6 State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University , Hong Kong, China.
  • 7 Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine , Shanghai, China.
  • 8 Institue of Experimental Immunology, University of Zurich , Zurich, Switzerland.
  • 9 State Key Laboratory of Liver Research, The University of Hong Kong , Hong Kong, China.
  • 10 The University of Hong Kong - Shenzhen Hospital , Shenzhen, China.
  • 11 International Cancer Institute and State Key Laboratory of Molecular Oncology, Peking University , Beijing, China.
  • 12 MOE Frontiers Science Center for Cancer Integrative Omics, Peking University , Beijing, China.
  • 13 Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
PMID: 39636298 DOI: 10.1084/jem.20241442
Abstract

Tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the Cancer type. Here, we showed that TANs affect metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma (MASH-related HCC) more than viral-associated HCC. We attributed this difference to the predominance of SiglecFhi TANs in MASH-related HCC tumors. Linoleic acid and GM-CSF, which are commonly elevated in the MASH-related HCC microenvironment, fostered the development of this c-Myc-driven TAN subset. Through TGFβ secretion, SiglecFhi TANs promoted HCC stemness, proliferation, and migration. Importantly, SiglecFhi TANs supported immune evasion by directly suppressing the antigen presentation machinery of tumor cells. SiglecFhi TAN removal increased the immunogenicity of a MASH-related HCC model and sensitized it to immunotherapy. Likewise, a high SiglecFhi TAN signature was associated with poor prognosis and immunotherapy resistance in HCC patients. Overall, our study highlights the importance of understanding TAN heterogeneity in Cancer to improve therapeutic development.

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