2. Academic Validation
  3. HMOX1+ macrophages determine immunosuppressive microenvironment and immunotherapy efficacy in hepatocellular carcinoma

HMOX1+ macrophages determine immunosuppressive microenvironment and immunotherapy efficacy in hepatocellular carcinoma

  • Hepatol Commun. 2025 Oct 14;9(11):e0815. doi: 10.1097/HC9.0000000000000815.
Yabing Du 1,  Wenxin Xu 2,  Zhenkun Liu 1,  Peihao Wen 3,  Ruifeng Song 4,  Weiwei Hao 4,  Yating Liu 5,  Xinlei Zhao 6,  Meiying Gu 1,  Jialei Weng 7,  Wei He 1
Affiliations

Affiliations

  • 1 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China.
  • 2 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
  • 3 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, P.R. China.
  • 4 Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P.R. China.
  • 5 Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
  • 6 Institute for Pathology, University Hospital of Cologne, Cologne, Germany.
  • 7 Department of Surgical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
PMID: 41085544 DOI: 10.1097/HC9.0000000000000815
Abstract

Background: HCC is a notably immunosuppressive malignancy with limited therapeutic options and poor prognosis. Macrophages, as major immune cell populations within the tumor microenvironment, significantly influence disease progression and therapy efficacy. We aim to identify pivotal macrophage subsets associated with HCC progression and resistance to immunotherapy.

Methods: Immunotherapy-associated macrophage-specific marker genes were identified by single-cell RNA-sequencing analysis and transcriptome analysis. The clinical relevance of macrophages with heme oxygenase 1 (HMOX1) positive was assessed in HCC patients by immunofluorescence. The immune microenvironment of HCC and the functional phenotype of HMOX1+ macrophages were explored using cytometry by time-of-flight (CyTOF).

Results: Single-cell RNA-sequencing analyses revealed that HMOX1 was predominantly expressed in intratumoral macrophages within the HCC microenvironment. Intratumoral HMOX1+ macrophages abundance was associated with worse prognosis and immunotherapy efficacy in patients with HCC. CyTOF analysis showed that the HCC microenvironment with high infiltration of HMOX1+ macrophages was characterized by high infiltration of CD4+ regulatory T cells (Tregs) and high expression of programmed death-1 (PD-1) in CD8+ T cells. Besides, HMOX1+ macrophages exhibited an immunosuppressive functional state. Pharmacological inhibition of HMOX1 by Znpp enhanced the therapeutic efficacy of anti-PD-1 antibody in the HCC mouse model.

Conclusions: Macrophage-specific HMOX1 serves as a novel biomarker for predicting the efficacy of immunotherapy, and targeting HMOX1 has the potential to enhance the efficacy of anti-PD-1 therapy in HCC patients.

Keywords

HCC; heme oxygenase-1; immunotherapy; macrophages; tumor microenvironment.

Figures
Products