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

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.