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<p>Tumor-associated macrophages are a key component that contributes to the immunosuppressive microenvironment in human cancers. However, therapeutic targeting of macrophages has been a challenge in clinic due to the limited understanding of their heterogeneous subpopulations and distinct functions. Here, we identify a clinically relevant CD19<sup>+</sup> subpopulation of macrophages that is enriched in many types of cancer, particularly in hepatocellular carcinoma (HCC). The CD19<sup>+</sup> macrophages exhibit increased levels of programmed cell death 1 ligand 1 (PD-L1) and CD73, enhanced mitochondrial oxidation, and compromised phagocytosis, indicating their immunosuppressive functions. Targeting CD19<sup>+</sup> macrophages with anti-CD19 chimeric antigen receptor T (CAR-T) cells inhibited HCC tumor growth. We identify Paired Box 5 (PAX5) as a primary driver of up-regulated mitochondrial biogenesis in CD19<sup>+</sup> macrophages, which depletes cytoplasmic Ca<sup>2+</sup>, leading to lysosomal deficiency and consequent accumulation of CD73 and PD-L1. Inhibiting CD73 or mitochondrial oxidation enhanced the efficacy of immune checkpoint blockade therapy in treating HCC, suggesting great promise for CD19<sup>+</sup> macrophage-targeting therapeutics.</p>

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Tumor-associated CD19+ macrophages induce immunosuppressive microenvironment in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月26日

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  • Junli Wang,
  • Wanyue Cao,
  • Jinyan Huang,
  • Yu Zhou,
  • Rujia Zheng,
  • Yu Lou,
  • Jiaqi Yang,
  • Jiawei Yan,
  • Jianghui Tang,
  • Mao Ye,
  • Zhengtao Hong,
  • Jiangchao Wu,
  • Haonan Ding,
  • Yuquan Zhang,
  • Jianpeng Sheng,
  • Xinjiang Lu,
  • Pinglong Xu,
  • Xiongbin Lu,
  • Xueli Bai,
  • Tingbo Liang,
  • Qi Zhang

摘要

Tumor-associated macrophages are a key component that contributes to the immunosuppressive microenvironment in human cancers. However, therapeutic targeting of macrophages has been a challenge in clinic due to the limited understanding of their heterogeneous subpopulations and distinct functions. Here, we identify a clinically relevant CD19+ subpopulation of macrophages that is enriched in many types of cancer, particularly in hepatocellular carcinoma (HCC). The CD19+ macrophages exhibit increased levels of programmed cell death 1 ligand 1 (PD-L1) and CD73, enhanced mitochondrial oxidation, and compromised phagocytosis, indicating their immunosuppressive functions. Targeting CD19+ macrophages with anti-CD19 chimeric antigen receptor T (CAR-T) cells inhibited HCC tumor growth. We identify Paired Box 5 (PAX5) as a primary driver of up-regulated mitochondrial biogenesis in CD19+ macrophages, which depletes cytoplasmic Ca2+, leading to lysosomal deficiency and consequent accumulation of CD73 and PD-L1. Inhibiting CD73 or mitochondrial oxidation enhanced the efficacy of immune checkpoint blockade therapy in treating HCC, suggesting great promise for CD19+ macrophage-targeting therapeutics.