2. Academic Validation
  3. GPR34 inhibition reprograms tumor-associated macrophages and enhances the sensitivity of anti-PD-1 therapy in hepatocellular carcinoma

GPR34 inhibition reprograms tumor-associated macrophages and enhances the sensitivity of anti-PD-1 therapy in hepatocellular carcinoma

  • Cancer Cell Int. 2025 Nov 21;25(1):419. doi: 10.1186/s12935-025-04030-3.
Wenfeng Liu # 1 2,  Qiang Yu # 3,  Xinyi Liu # 1 2,  Feng Zhang 1 2,  Qiuyu Jiang 1 2,  Wenqing Tang 1 2,  Ling Dong 4 5
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, P.R. China.
  • 2 Shanghai Institute of Liver Disease, 180 Fenglin Road, Shanghai, 200032, P.R. China.
  • 3 Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Fudan University, Ministry of Education, Shanghai, 200032, P.R. China.
  • 4 Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, P.R. China. [email protected].
  • 5 Shanghai Institute of Liver Disease, 180 Fenglin Road, Shanghai, 200032, P.R. China. [email protected].
  • # Contributed equally.
PMID: 41272735 DOI: 10.1186/s12935-025-04030-3
Abstract

Background: Macrophage play a dual role in tumor progression. However, the mechanisms underlying tumor-associated macrophage (TAM) polarization in the hepatocellular carcinoma (HCC) microenvironment remain elusive.

Methods: We analyzed the proportions of tumor-infiltrating immune cells in The Cancer Genome Atlas Liver Hepatocellular Carcinoma cohort. Subsequently, a risk prediction model was constructed for patients with HCC. The expression patterns and clinical relevance of G protein-coupled receptor 34 (GPR34) were evaluated. The potential functions and mechanisms of GPR34 in macrophages were also investigated. Additionally, HCC mouse models were used to assess the therapeutic potential of a GPR34 inhibitor in enhancing immune checkpoint blockade (ICB) therapy.

Results: A novel prognostic prediction model based on macrophage-related genes was established to predict the outcomes of patients with HCC. In this model, GPR34 was identified as significantly upregulated and associated with a poor clinical prognosis in HCC. Mechanistically, GPR34 facilitated M2 macrophage polarization by activating the PI3K/Akt signaling axis. The pharmacological inhibition of GPR34 effectively suppressed tumor growth. Moreover, the combination of a GPR34 inhibitor with a PD-1 inhibitor demonstrated synergistic antitumor effects.

Conclusion: GPR34 is pivotal in driving macrophage M2 polarization, and inhibitor targeting GPR34 represents promising antitumor agent capable of augmenting the efficacy of anti-PD-1 therapy.

Keywords

GPR34; Hepatocellular carcinoma; Immune checkpoint blockade.

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