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

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.