{
  "abstract": "Background Insufficient infiltration of CD8 + T cells in the tumor microenvironment (TME) critically restricts antitumor immunity and cancer immunotherapy efficacy. The purpose of this study was to identify novel tumor cell-intrinsic regulators of T-cell infiltration and to elucidate their mechanisms of action.Methods We performed a genome-wide Sleeping Beauty transposon mutagenesis screen in murine breast cancer models. Protein–protein interactions were identified by mass spectrometry and validated by co-immunoprecipitation. Gene and protein expression levels were assessed by reverse transcription and quantitative PCR and western blotting. T-cell infiltration and function were evaluated using flow cytometry, immunohistochemistry (IHC), multiplex IHC, and by analyzing bulk and single-cell RNA sequencing data complemented by bioinformatic analysis. The specific dephosphorylation sites on LGALS1 were confirmed through phosphomimetic mutant experiments. T-cell infiltration was further validated using an in vitro T-cell transendothelial migration assay and in vivo mouse models.Results Our screening identified 39 candidate genes, with tumor cell-intrinsic dual-specificity phosphatase 22 (DUSP22) expression correlating with enhanced CD8 + T-cell accumulation and suppressed tumor progression. Overexpression of DUSP22 resulted in increased CD8+ T-cell infiltration and enhanced T-cell function. Mechanistically, DUSP22 binds to LGALS1 and dephosphorylates it at the Ser8 and Thr58 residues, leading to LGALS1 degradation and subsequent alleviation of LGALS1-mediated immunosuppression. In human breast cancer samples, LGALS1 expression was negatively correlated with both DUSP22 levels and CD8+ T-cell infiltration. Therapeutic targeting of the DUSP22-LGALS1 axis significantly enhanced CD8+ T-cell infiltration and synergized with anti-programmed cell death protein-1 therapy to boost antitumor responses.Conclusions Our findings unveil a novel phosphorylation-dependent DUSP22-LGALS1 axis that reprograms the immunosuppressive TME. This work thus proposes a promising therapeutic strategy to overcome immune checkpoint blockade resistance in breast cancer.",
  "authors": [
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Lijian Wang"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Yutong Guo"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Yujie Dai"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Wangsheng Sun"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Xiaoying Huang"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Haipeng Lei"
    },
    {
      "affiliations": [
        "Division of Hepatobiliary & Pancreatic, Department of Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China"
      ],
      "name": "Aiping Zhang"
    },
    {
      "affiliations": [
        "School of Pharmacy, Laboratory of Drug Discovery from Natural Resources and Industrialization, State Key Laboratory of Mechanism and Quality of Chines Medicine, Macau University of Science and Technology, Macau, People's Republic of China"
      ],
      "name": "Shuwen Chen"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Yiting Li"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Jiani Pan"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Yangjian Hong"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Lingchuan Ma"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Zhuhai UM Science & Technology Research Institute, Zhuhai, People's Republic of China"
      ],
      "name": "Yangyang Feng"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Fangyuan Shao"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Jianming Zeng"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Peng Luo"
    },
    {
      "affiliations": [
        "Clinical Research and Translational Medicine Department, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China",
        "Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, People's Republic of China"
      ],
      "name": "Junqi LI"
    },
    {
      "affiliations": [
        "School of Life Sciences, Jiaying University, Meizhou, People's Republic of China"
      ],
      "name": "Weiting Chen"
    },
    {
      "affiliations": [
        "School of Pharmacy, Laboratory of Drug Discovery from Natural Resources and Industrialization, State Key Laboratory of Mechanism and Quality of Chines Medicine, Macau University of Science and Technology, Macau, People's Republic of China"
      ],
      "name": "Na Zhou"
    },
    {
      "affiliations": [
        "Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital, and Institute of Immunology, Jilin University, Changchun, People's Republic of China"
      ],
      "name": "Yang Li"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Heng Sun"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Xiaoling Xu"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Chu-Xia Deng"
    },
    {
      "affiliations": [
        "Cancer Center, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, People's Republic of China",
        "MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau, People's Republic of China"
      ],
      "name": "Kai Miao"
    }
  ],
  "title": "DUSP22 dephosphorylates LGALS1 to enhance T cell-driven antitumor immunity",
  "uid": "7fd52e7a-bf40-573c-bb2d-c13bfdbddca7"
}