{
  "abstract": "Background Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed death ligand-1 signaling induce tumor regression in some patients with NSCLC, but most patients with NSCLC exhibit resistance to ICIs therapy. NSCLC shapes the potent tumor immunosuppressive microenvironment (TIME) that underlies tumor immune tolerance and acquired resistance. Therefore, elucidating the cellular and molecular mechanisms by which NSCLC establishes and sustains the TIME is essential for developing novel strategies to overcome immune resistance and enhance the clinical benefit of ICIs.Methods The correlation between sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) expression and ICIs was analyzed via immunohistochemistry. Cell migration assay was performed to assess the effect of SAMHD1 on macrophage recruitment. Multicolor flow cytometry was performed to analyze the effect of SAMHD1 knockdown on the tumor microenvironment. SAMHD1 regulation of the dual specificity phosphatase 6-extracellular regulated protein kinases 1/2 (DUSP6-ERK1/2) pathway was verified by RNA sequencing and western blotting.Results Here, we identify the SAMHD1 as a potential therapeutic target and a major determinant of poor response to ICIs in patients with NSCLC. Tumors with high SAMHD1 expression show resistance to anti-PD-1 antibody (αPD-1) treatment, whereas tumors with low SAMHD1 expression are highly sensitive. SAMHD1-dependent resistance to αPD-1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, SAMHD1 regulates the expression of macrophage-associated chemokines by influencing the activation of the DUSP6-ERK1/2 pathway, which contributes to TAMs aggregation within NSCLC tumors to shape an immunosuppressive microenvironment. The HIV accessory protein viral protein-x (VPX) specifically degrades SAMHD1 to promote HIV replication. Similarly, the vpx-engineered oncolytic adenovirus (oAd-vpx) targets SAMDH1 degradation to enhance oncolytic adenovirus replication and weaken the hostile immune microenvironment shaped by TAMs, thereby triggering a CD8+T-cell-dependent antitumor immune response. The combination of oAd-vpx and αPD-1 inhibits tumor growth and enhances sensitivity to ICIs in both mouse and human NSCLC.Conclusions This research identifies a key mechanism of SAMHD1-driven immunosuppression and highlights its important role in oncolytic adenovirus therapy. This study provides a theoretical basis for targeting SAMHD1 as a drug therapy strategy in patients with NSCLC.",
  "authors": [
    {
      "affiliations": [
        "Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China"
      ],
      "name": "Shichuan Hu"
    },
    {
      "affiliations": [
        "Department of Oncology & Department of Pathology, The Second People's Hospital of Neijiang, Sichuan, China",
        "Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China"
      ],
      "name": "Jian Xu"
    },
    {
      "affiliations": [
        "Hebei Key Laboratory of Molecular Oncology & Department of Chemoradiotherapy, Tangshan People’s Hospital, Hebei, China"
      ],
      "name": "Zhiwu Wang"
    },
    {
      "affiliations": [
        "Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China"
      ],
      "name": "Yong Zhang"
    },
    {
      "affiliations": [
        "Department of Oncology & Department of Pathology, The Second People's Hospital of Neijiang, Sichuan, China"
      ],
      "name": "Chang Zhao"
    },
    {
      "affiliations": [
        "Department of Oncology & Department of Pathology, The Second People's Hospital of Neijiang, Sichuan, China"
      ],
      "name": "Yu Liu"
    },
    {
      "affiliations": [
        "Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China"
      ],
      "name": "Feng Luo"
    },
    {
      "affiliations": [
        "Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China"
      ],
      "name": "Ping Cheng"
    },
    {
      "affiliations": [
        "Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China",
        "Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China"
      ],
      "name": "Jiantao Wang"
    },
    {
      "affiliations": [
        "Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China"
      ],
      "name": "Jing Zhao"
    }
  ],
  "title": "SAMHD1 drives immunosuppression in non-small cell lung cancer by promoting macrophage infiltration and restricting oncolytic adenovirus replication",
  "uid": "6d92bc30-e7ce-5677-98e5-2287d5addd2b"
}