Plasmacytoid dendritic cells (pDCs) play immunosuppressive roles in the tumor microenvironment (TME). However, the molecular mechanisms underlying the recruitment and dysfunction of pDCs in the TME remain largely elusive, especially in hepatocellular carcinoma (HCC). In this study, we observed the accumulation of pDCs in the blood, tumor tissue, and ascitic fluid of HCC patients. A high density of tumor-infiltrating pDCs was correlated with poor prognosis in patients with HCC. Hypoxia-induced extracellular adenosine (eADO) significantly enhanced pDC recruitment into tumors via the adenosine A1 receptor (ADORA1). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transcriptionally upregulated the expression of the ectonucleotidases CD39 and CD73 in HCC cells, both of which are essential for the generation of eADO. Moreover, eADO-stimulated pDCs promoted the induction of regulatory T cells and suppressed proliferation and cytotoxicity of CD8⁺ T cells. Depletion of pDCs using a monoclonal antibody or an ADORA1 antagonist significantly improved antitumor immunity and suppressed HCC growth in the immunocompetent HCC mouse model. Thus, targeting pDC recruitment may serve as a potential adjuvant strategy for immunotherapies in HCC.

浆细胞样树突状细胞 (pDC) 在肿瘤微环境 (TME) 中发挥免疫抑制作用。然而，TME 中 pDC 募集和功能障碍的分子机制在很大程度上仍然难以捉摸，尤其是在肝细胞癌 (HCC) 中。在这项研究中，我们观察到 pDC 在 HCC 患者的血液、肿瘤组织和腹水中的积累。高密度的肿瘤浸润 pDC 与 HCC 患者的不良预后相关。缺氧诱导的细胞外腺苷 (eADO) 通过腺苷 A1 受体 (ADORA1) 显着增强 pDC 募集到肿瘤中。从机制上讲，缺氧诱导因子 1-α (HIF-1α) 在 HCC 细胞中转录上调外核苷酸酶 CD39 和 CD73 的表达，这两者对于 eADO 的产生都是必不可少的。而且，⁺ T 细胞。在免疫活性 HCC 小鼠模型中，使用单克隆抗体或 ADORA1 拮抗剂去除 pDC 可显着提高抗肿瘤免疫力并抑制 HCC 生长。因此，靶向 pDC 募集可作为 HCC 免疫治疗的潜在辅助策略。