Abstract
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.
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The remaining data are available within the Article, Supplementary Information or Source Data file. Source data are provided with this paper. Any additional information required to reanalyze the data reported in this paper is always available from the lead contact upon request (Qi Zhang: qi.zhang@zju.edu.cn). For external requests for additional data or materials required to reproduce the results presented in this manuscript, the requester must submit a formal application stating the research purpose, intended use of the data, and commitment to abide by relevant data protection and ethical guidelines. Human sequencing data were deposited in Genome Sequence Archive (GSA) (https://ngdc.cncb.ac.cn/gsa-human/browse/HRA008143). All processed sequencing data are deposited in the Science Data Bank database, available via https://cstr.cn/31253.11.sciencedb.11557 or CSTR:31253.11.sciencedb.11557. Source data are provided with this paper.
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Acknowledgements
This work was supported by National Key Research & Development Program (No. 2020YFA0804300), National Natural Science Foundation of China (Nos. 82071865, 82403723, 81871320, 32321002, 82188102, 92359304), Zhejiang Provincial Natural Science Funds (Nos. LR20H160002, HDMD22H319373), Zhejiang Provincial Medical and Health Technology Project (No. WKJ-ZJ-2403), and Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project (No. GZY-ZJ-KJ-23025). We thank Jianfeng Wang from the Zhejiang Provincial Key Laboratory of Pancreatic Disease for sample collection. Dr. Qi Zhang also gratefully acknowledges the support of K.C. Wong Education Foundation.
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T.L. and Q.Z. conceived the project. Q.Z., J.W. and J.S. designed the experiments. Q.Z., J.W., W.C., Y.Z., JQ.Y., JW.Y., J.T., M.Y., Z.H., J.W., H.D., and YQ.Z. performed most of the experiments under the supervision of T.L., X.B., X.L. and P.X. R.Z., Y.L., X.L., and J.H. performed the bioinformatic analysis. Q.Z. and J.W. wrote the manuscript and the other authors made critical revisions.
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Wang, J., Cao, W., Huang, J. et al. Tumor-associated CD19+ macrophages induce immunosuppressive microenvironment in hepatocellular carcinoma. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69638-z
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DOI: https://doi.org/10.1038/s41467-026-69638-z
