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  3. PLAUR+ Neutrophils Drive Anti-PD-1 Therapy Resistance in Patients with Hepatocellular Carcinoma by Shaping an Immunosuppressive Microenvironment

PLAUR+ Neutrophils Drive Anti-PD-1 Therapy Resistance in Patients with Hepatocellular Carcinoma by Shaping an Immunosuppressive Microenvironment

  • Adv Sci (Weinh). 2025 Jul 17:e07167. doi: 10.1002/advs.202507167.
Shaoqing Liu 1 2,  Yanzhao Zhou 3,  Gaoxiang Li 4,  Bingwen Zhu 5,  Fang Wu 6,  Jinxue Zhou 7,  Xiaobing Chen 3,  Bo Qin 1,  Yanxia Gao 2 5,  Fazhan Wang 8,  Yong Jiang 2 5,  Wenxin Xu 1 9
Affiliations

Affiliations

  • 1 Department of Breast Surgery, Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China.
  • 2 State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Henan International Joint Laboratory of Infection and Immunity, Henan Key Laboratory of Critical Care Medicine, Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China.
  • 3 Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
  • 4 State Key Laboratory of Systems Medicine for Cancer, Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 5 Institute of Infection and Immunity, Henan Academy of Innovations in Medical Science, Zhengzhou, 451163, China.
  • 6 Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 7 Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
  • 8 Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450052, China.
  • 9 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, P. R. China.
PMID: 40673864 DOI: 10.1002/advs.202507167
Abstract

Hepatocellular carcinoma (HCC) is characterized by an immunosuppressive tumor microenvironment (TME) that limits the efficacy of immune checkpoint inhibitors. However, the role of distinct neutrophil subsets within the TME in mediating tumor resistance to immunotherapy remains poorly understood. Here, the present study reveals that the urokinase-type plasminogen activator receptor (PLAUR)+ neutrophils are enriched in immunotherapy non-responders and correlate with poor prognosis. Through multi-omics analyses of clinical cohorts and preclinical models, PLAUR+ neutrophils identify as a pivotal driver of immunotherapy resistance by shaping an immunosuppressive TME. Mechanistically, spatial transcriptomics and single-cell RNA Sequencing reveal that PLAUR+ neutrophils orchestrate immune evasion by CD8+ T cell exclusion and macrophage-dependent immune suppression. Through the structure-based virtual screening, a novel PLAUR inhibitor is identified that could reverse the immunosuppressive phenotype of neutrophils. In various in vivo tumor models, PLAUR inhibitor suppresses tumor growth and potentiates the efficacy of anti-programmed cell death protein 1 (PD-1) therapy. These results demonstrate that PLAUR+ neutrophils serve as a critical regulator of immunotherapy resistance and targeting PLAUR is a promising strategy to augment the efficacy of anti-PD-1 therapy in HCC.

Keywords

biomarker; hepatocellular carcinoma; immunotherapy; neutrophil; urokinase‐type plasminogen activator receptor.

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