{
  "abstract": "Background Neoadjuvant immunotherapy has reshaped the treatment paradigm for esophageal squamous cell carcinoma (ESCC), yet mechanisms of resistance in non-responders remain poorly understood. Specifically, the spatial orchestration of the tumor microenvironment that limits effective antitumor immunity is not fully elucidated.Methods Integrating spatial transcriptomic analysis with large-scale tissue pathology, we mapped the spatial architecture of the immune landscape in immunotherapy-resistant ESCC to identify cellular and molecular determinants of treatment failure.Results We revealed a distinct immune exclusion phenotype in non-responders, characterized by peritumoral CD8 + T cell enrichment coupled with intratumoral depletion. At the invasive front, we identified COL11A1+ cancer-associated fibroblasts (CAFs) and SPP1+ tumor-associated macrophages as spatially correlated markers of immune exclusion, demarcating regions characterized by limited T cell infiltration. Mechanistically, a distinct subpopulation of LAMC2+ tumor cells localized at the tumor boundary acts as the master orchestrator of this barrier. These LAMC2+ cells exhibit aberrant lactate metabolism and elevated stemness, driving CAF activation via Semaphorin 3C secretion. Strikingly, this ‘LAMC2+ boundary tumor cell-immune-privileged niche’ axis exhibits pan-cancer correlations with immunotherapy resistance, positioning LAMC2 as a robust predictive biomarker.Conclusion In this study, we identify the tumor invasive margin as a critical determinant of immunotherapy resistance in ESCC. By defining the specific spatial markers and molecular architecture of an immune-privileged niche associated with the immune-exclusion barrier, our findings demonstrate the value of spatially resolved microenvironmental analysis. Moreover, we propose that therapeutic targeting of this boundary niche represents a promising strategy to overcome resistance in ESCC.",
  "authors": [
    {
      "affiliations": [
        "The Comprehensive Cancer Center, Department of Central Laboratory, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China",
        "Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Huai'an, Jiangsu, China"
      ],
      "name": "Li Wan"
    },
    {
      "affiliations": [
        "School of Mathematics and Statistics, Taishan University, Tai’an, Shandong, China"
      ],
      "name": "Boye Li"
    },
    {
      "affiliations": [
        "Department of Oncology, Huai’an Hospital Affiliated to Yangzhou University (The Fifth People’s Hospital of Huai’an), Huaian, Jiangsu, China"
      ],
      "name": "Tianyun Ma"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Min Wang"
    },
    {
      "affiliations": [
        "The Comprehensive Cancer Center, Department of Central Laboratory, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China",
        "Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Huai'an, Jiangsu, China"
      ],
      "name": "Fei Xie"
    },
    {
      "affiliations": [
        "The Comprehensive Cancer Center, Department of Central Laboratory, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China",
        "Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Huai'an, Jiangsu, China"
      ],
      "name": "Haotian Ge"
    },
    {
      "affiliations": [
        "School of Mathematics and Statistics, Taishan University, Tai’an, Shandong, China"
      ],
      "name": "Zixuan Xiao"
    },
    {
      "affiliations": [
        "School of Mathematics and Statistics, Taishan University, Tai’an, Shandong, China"
      ],
      "name": "Xinyi Chen"
    },
    {
      "affiliations": [
        "School of Mathematics and Statistics, Taishan University, Tai’an, Shandong, China"
      ],
      "name": "Lingda Meng"
    },
    {
      "affiliations": [
        "The Comprehensive Cancer Center, Department of Central Laboratory, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China",
        "Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Huai'an, Jiangsu, China"
      ],
      "name": "Li Zhang"
    },
    {
      "affiliations": [
        "The Comprehensive Cancer Center, Department of Central Laboratory, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China",
        "Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Kunxin Xie"
    },
    {
      "affiliations": [
        "The Comprehensive Cancer Center, Department of Central Laboratory, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China",
        "Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Huai'an, Jiangsu, China"
      ],
      "name": "Qilong Wang"
    }
  ],
  "title": "An Immune-privileged niche mediates immunotherapy resistance in esophageal carcinoma",
  "uid": "1d31d7be-5339-50f2-a212-4123e4e9e5b6"
}