{
  "abstract": "While radiotherapy (RT) is effective for local tumor control, it rarely induces the regression of non-irradiated metastases, a phenomenon known as the abscopal effect. The mechanisms constraining this systemic immune response remain poorly understood. This study investigates galectin-9 (Gal-9), a ligand for the TIM-3 (T-cell immunoglobulin and mucin-domain containing-3) immune checkpoint, as a mediator of immune escape that limits RT systemic efficacy and evaluates combinatorial RT/Gal-9 blockade in preclinical models.Background Methods Multiplatform analysis (RNA sequencing, immunoblot, flow cytometry, ELISA, immunohistochemistry) characterized RT-induced Gal-9 regulation in human lung/colorectal cancer cell lines, murine tumors/serums, and paired patient tumors. Local and abscopal therapeutic efficacy was evaluated in homologous (CT26/CT26, LLC/LLC) and heterologous (CT26/4T1) two-tumor mouse models. Immune profiling of tumor microenvironment, tumor-draining lymph nodes (tdLNs), and splenic compartments was comprehensively assessed by flow cytometry. Mechanistic studies employed STING (Stimulator of Interferon Genes) inhibition (H151), CD8 + T-cell depletion (anti-CD8α), macrophage/monocyte depletion (PLX-3397), interferon-I (IFN-I) blockade (anti-IFNAR1), and lymphocyte egress inhibition (FTY720).Results RT upregulated Gal-9 predominantly within host myeloid compartments (dendritic cells, macrophages, monocytes, neutrophils) versus tumor cells, in both irradiated tumors and abscopal tumors. Mechanistically, RT-activated STING-IFN-I axis locally induced Gal-9 + myeloid cells that subsequently disseminated systemically. Clinically, elevated post-RT Gal-9 in patient biopsies correlated with poor therapeutic outcomes. Notably, combining Gal-9 blockade with RT elicited potent abscopal responses in homologous two-tumor mouse models. Furthermore, anti-Gal-9 markedly enhanced radio-immunotherapy efficacy in the poorly immunogenic Lewis lung carcinoma. Immunologically, Gal-9 blockade synergized with RT to activate the myeloid and T cell compartments, enhancing dendritic cell accumulation in tdLNs and boosting CD8+ T cell infiltration in abscopal tumors. Depletion of CD8+ T cells/monocytes or blocking lymphocyte egress from lymph nodes abrogated the abscopal efficacy, underscoring their essential roles.Conclusions Our findings establish RT-induced Gal-9 as a novel dual myeloid/T-cell immune checkpoint restricting abscopal responses. Gal-9 blockade represents a promising strategy to potentiate radiotherapy against metastatic disease, defining a therapeutic paradigm distinct from conventional checkpoint inhibitors.",
  "authors": [
    {
      "affiliations": [
        "Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China",
        "Department of Lung Cancer Surgery, Center of Thoracic Surgery, Tianjin Medical University General Hospital, Tianjin, China"
      ],
      "name": "Jiaming Song"
    },
    {
      "affiliations": [
        "Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"
      ],
      "name": "Boning Liu"
    },
    {
      "affiliations": [
        "Radiation Oncology, Medical Imaging and Radiological Science, and Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital Linkou, Taoyuan City, Taiwan"
      ],
      "name": "Rodney Cheng-En Hsieh"
    },
    {
      "affiliations": [
        "Graduate Institute of Cell Biology, China Medical University, Taichung, Taiwan"
      ],
      "name": "Hsiao-Fan Chen"
    },
    {
      "affiliations": [
        "Departments of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA",
        "The AHMC Dermatology and Research Center, Arcadia, California, USA"
      ],
      "name": "Riyao Yang"
    },
    {
      "affiliations": [
        "Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China"
      ],
      "name": "Jinjian Liu"
    },
    {
      "affiliations": [
        "Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"
      ],
      "name": "Zhiguo Liu"
    },
    {
      "affiliations": [
        "Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"
      ],
      "name": "Shasha Shi"
    },
    {
      "affiliations": [
        "Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"
      ],
      "name": "Qihui Chen"
    },
    {
      "affiliations": [
        "Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"
      ],
      "name": "Delong Liu"
    },
    {
      "affiliations": [
        "Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"
      ],
      "name": "Shunjie Xiong"
    },
    {
      "affiliations": [
        "Departments of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA",
        "Graduate Institute of Biomedical Sciences, Graduate Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan"
      ],
      "name": "Mien-Chie Hung"
    },
    {
      "affiliations": [
        "Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"
      ],
      "name": "Linlin Sun"
    }
  ],
  "title": "Galectin-9-driven immune evasion constrains radiotherapy-induced systemic antitumor immunity",
  "uid": "96a8afed-52cc-5ba8-a13f-e4a9d42e5016"
}