{
  "abstract": "Background Tumor-associated macrophages are pivotal drivers of hepatocellular carcinoma (HCC) progression. However, the functional contributions of proliferating macrophages (Prolif Ms) within the tumor microenvironment (TME) remain poorly defined.Methods Here, we integrated single-cell RNA sequencing, Cleavage Under Targets and Tagmentation (CUT&Tag), bulk RNA sequencing, multiparametric immunofluorescence, flow cytometry, and molecular dynamics simulation to dissect the phenotype, functional landscape, and targeting strategy of Prolif Ms in HCC.Results We identified a novel Prolif Ms subset characterized by high expression of proliferation markers (Cdk1, Mki67), distinct from classical M1/M2 macrophages. Mechanistically, ribonuclease H2 subunit C (Rnaseh2c) acts as a non-enzymatic regulator, binding directly to the cyclin-dependent kinase promoter to drive macrophage proliferation while suppressing endocytic and antigen-presenting capabilities. Rnaseh2c further promotes CD8 + exhausted T cell (CD8+ Tex) infiltration via the C-C motif chemokine ligand 2/C-C motif chemokine receptor type 2 (CCL2/CCR2) axis, fostering an immunosuppressive TME. Notably, Rnaseh2c exhibits cancer-promoting effects in both macrophages and hepatocytes. We developed a specific inhibitor “Rnaseh2c-In1”, which inhibits HCC growth by reducing CCL2 secretion and CD8+ Tex infiltration, demonstrating favorable pharmacokinetics and low toxicity.Conclusions This study elucidates a non-enzymatic Rnaseh2c-driven mechanism regulating Prolif Ms, providing a novel therapeutic target and candidate compound for HCC treatment.",
  "authors": [
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China"
      ],
      "name": "Zengbin Wang"
    },
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China"
      ],
      "name": "Ruiying Xiao"
    },
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China"
      ],
      "name": "Mengxin Liu"
    },
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China"
      ],
      "name": "Lihua Ceng"
    },
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China"
      ],
      "name": "Zikun Lin"
    },
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China"
      ],
      "name": "Xinyu Zheng"
    },
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China"
      ],
      "name": "Miaoxin Shi"
    },
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China"
      ],
      "name": "Hong Ye"
    },
    {
      "affiliations": [
        "Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China"
      ],
      "name": "Linqing Wu"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China",
        "Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China",
        "Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China",
        "Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou, China"
      ],
      "name": "Nanhong Tang"
    }
  ],
  "title": "Non-enzymatic Rnaseh2c orchestrates proliferating macrophage-driven immunosuppression and HCC progression via Cdk9 proliferation axis and CCL2/CCR2-mediated CD8+ Tex infiltration: a novel therapeutic paradigm with “Rnaseh2c-In1” inhibitor",
  "uid": "1a67c01a-240c-5b98-b06b-252d4880276e"
}