{
  "abstract": "Background Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited responses to immunotherapy, largely due to its uniquely immunosuppressive tumor microenvironment (TME). However, the molecular mechanisms driving this phenotype remain incompletely understood.Methods We integrated single-cell RNA sequencing and Xenium in situ spatial transcriptomics to analyze the immune microenvironment of five SCLC and four non-small cell lung cancer (NSCLC) samples. Multiplex immunofluorescence was used to validate cell types and gene expression in the same tissue specimens, and animal models were employed to verify the key mechanistic pathway.Results SCLC displayed a distinct immune landscape compared with NSCLC, with increased infiltration of C-X-C motif chemokine receptor 4 (CXCR4) + neutrophils (via neutrophil extracellular traps) and S100A8+ monocytes (toward an M2-like phenotype), and reduced CD8+ T-cell infiltration. Malignant epithelial cells in SCLC highly expressed CXCR4, regulated by transcription factors ISL LIM homeobox 1 and distal-less homeobox 5, which promoted immunosuppression. The C-X-C motif chemokine ligand 12 (CXCL12)–CXCR4 axis mediated competitive inhibition, impairing T-cell recruitment while enhancing neutrophil accumulation. Monocytes in SCLC shifted toward an M2-like phenotype, weakening antigen presentation. Xenium spatial transcriptomics confirmed colocalization of CXCR4+ neutrophils and S100A8+ monocytes with tumor cells at the tumor-normal interface, while CD8+ T cells were spatially segregated. In vivo experiments showed that CXCR4 inhibition reduced SCLC tumor growth, decreased immunosuppressive cell infiltration, and enhanced CD8+ T-cell accumulation.Conclusions The CXCL12–CXCR4 axis, together with immunosuppressive CXCR4 + neutrophils and S100A8+ monocytes, is a key driver of the immune-desert phenotype in SCLC. Targeting this axis holds promise as a therapeutic strategy to remodel the immunosuppressive TME and improve the efficacy of immunotherapy for SCLC.",
  "authors": [
    {
      "affiliations": [
        "Department of Oncology, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China"
      ],
      "name": "Peng Zeng"
    },
    {
      "affiliations": [
        "Department of Hepato-Pancreatico-Biliary Surgery, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China"
      ],
      "name": "Hai-Feng Li"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, Nanchang University Second Affiliated Hospital, Nanchang, Jiangxi, China"
      ],
      "name": "Wen-Bin Shu"
    },
    {
      "affiliations": [
        "Southeast University School of Medicine, Nanjing, Jiangsu, China"
      ],
      "name": "Jing Zhang"
    },
    {
      "affiliations": [
        "University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, USA"
      ],
      "name": "Tian-Cheng Zhao"
    },
    {
      "affiliations": [
        "Department of Hepato-Pancreatico-Biliary Surgery, Nanchang University Second Affiliated Hospital, Nanchang, Jiangxi, China"
      ],
      "name": "Jun-Wen Hu"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China"
      ],
      "name": "Jun-Fu Wang"
    },
    {
      "affiliations": [
        "Southeast University School of Medicine, Nanjing, Jiangsu, China"
      ],
      "name": "Cheng Wang"
    },
    {
      "affiliations": [
        "Southeast University School of Medicine, Nanjing, Jiangsu, China"
      ],
      "name": "Qing-Yun Lu"
    },
    {
      "affiliations": [
        "Southeast University School of Medicine, Nanjing, Jiangsu, China"
      ],
      "name": "Jia-Hui Yang"
    },
    {
      "affiliations": [
        "Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China"
      ],
      "name": "Yan-Li An"
    },
    {
      "affiliations": [
        "Department of Radiotherapy, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China"
      ],
      "name": "Rong Chen"
    }
  ],
  "title": "Single-cell and spatial transcriptomics reveal that the CXCL12–CXCR4 axis drives the immune-desert phenotype in small cell lung cancer by recruiting immunosuppressive CXCR4+ neutrophils and S100A8+ monocytes",
  "uid": "72682e10-3a32-5b52-ae02-2a0a33cee7d3"
}