{
  "abstract": "Background LKB1 (STK11)-deficient tumors exhibit an immunosuppressive microenvironment that limits the efficacy of immunotherapies such as anti-programmed cell death protein 1 (PD-1) antibodies. However, the underlying mechanisms driving immune evasion remain unclear. Dendritic cells (DCs), especially conventional DC 1 (cDC1), play a crucial role in antigen presentation and CD8 + T-cell activation, yet their dysfunction in LKB1-deficient tumors has not been well characterized.Methods Tumor-intrinsic LKB1 deficiency was modeled by subcutaneous inoculation of CRISPR/Cas9-engineered Stk11-knockout tumor cell lines into syngeneic mice. DC infiltration and function were assessed through a series of flow cytometry-based in vivo and in vitro assays, including analyses of infiltration, migration, antigen uptake, maturation, and CD8+ T-cell priming. Naïve CD8+ T-cell activation by cDC1s was evaluated via adoptive transfer of CD45.1+ OT-I T cells. Secretome proteomics and functional rescue experiments identified anterior gradient 2 (AGR2) as a key immunosuppressive mediator, and arginase 1 (ARG1) was validated as its functional interactor through liquid chromatography-tandem mass spectrometry (LC-MS/MS), co-immunoprecipitation, and imaging flow cytometry. Upstream regulation of AGR2 was investigated by AMPKα/FOXA1 silencing and chromatin immunoprecipitation (ChIP) quantitative PCR, revealing a tumor-intrinsic AMPKα–FOXA1–AGR2 axis driving DC dysfunction.Results LKB1-deficient tumors exhibited significantly reduced cDC1 infiltration, and cDC1s were functionally impaired in antigen uptake, migration, and naïve CD8 + T-cell priming. AGR2, a secreted protein transcriptionally upregulated via the tumor-intrinsic AMPKα–FOXA1 pathway, was identified as a key mediator of DC dysfunction. Mechanistically, AGR2 interacted with ARG1, stabilizing its expression and promoting ARG1 accumulation in DCs. Restoring DC infiltration and activity through FLT3L-driven expansion and tumor-antigen–specific DC supplementation significantly enhanced the efficacy of anti-PD-1 treatment in LKB1-deficient lung adenocarcinoma models.Conclusion Our study identifies profound DC dysfunction—characterized by impaired antigen uptake, migration, and naïve CD8 + T-cell priming—as a key mechanism of immune evasion in LKB1-deficient tumors. This dysfunction is driven by tumor-secreted AGR2, which stabilizes ARG1 in DCs and suppresses CD8+ T-cell activation. Targeting the AMPKα–FOXA1–AGR2–ARG1 axis or restoring DC competence offers a promising strategy to enhance immunotherapy efficacy in LKB1-deficient subtype.",
  "authors": [
    {
      "affiliations": [
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Department of Thoracic Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China",
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China"
      ],
      "name": "Yuxin Yao"
    },
    {
      "affiliations": [
        "Beijing Jishuitan Hospital, Department of Orthopaedic Oncology Surgery",
        "Beijing Research Institute of Traumatology and Orthopaedics, Capital Medical University, Beijing, China",
        "National Center for Orthopedics, Capital Medical University, Beijing, China"
      ],
      "name": "Yuejun Luo"
    },
    {
      "affiliations": [
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Department of Thoracic Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China",
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China"
      ],
      "name": "Zhanyu Wang"
    },
    {
      "affiliations": [
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Department of Thoracic Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China",
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China"
      ],
      "name": "Enzhi Yin"
    },
    {
      "affiliations": [
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Department of Thoracic Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China",
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China"
      ],
      "name": "Chengming Liu"
    },
    {
      "affiliations": [
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Department of Thoracic Surgery",
        "State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China",
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Office for Cancer Diagnosis and Treatment Quality Control, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China"
      ],
      "name": "Sufei Zheng"
    },
    {
      "affiliations": [
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Department of Thoracic Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China",
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China"
      ],
      "name": "Xinfeng Wang"
    },
    {
      "affiliations": [
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Department of Thoracic Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China",
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China"
      ],
      "name": "Xiaoya Tang"
    },
    {
      "affiliations": [
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Department of Thoracic Surgery",
        "State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China",
        "Henan academy of Innovations in Medical Science, Zhengzhou, Henan, China"
      ],
      "name": "Nan Sun"
    },
    {
      "affiliations": [
        "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Department of Thoracic Surgery",
        "State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China",
        "Henan academy of Innovations in Medical Science, Zhengzhou, Henan, China"
      ],
      "name": "Jie He"
    }
  ],
  "title": "Tumor-secreted AGR2 induces dendritic cell dysfunction and impairs immunotherapy efficacy in LKB1-deficient cancer",
  "uid": "381ab452-000b-5d0b-b4cc-9e5bee6d84c7"
}