{
  "abstract": "Background Combining chemotherapy with anti-programmed cell death protein-1 (PD-1) improves clinical outcomes in oesophageal squamous cell carcinoma (ESCC), yet the underlying synergistic mechanism remains obscured. Moreover, 30–50% of patients still derive no therapeutic benefit from the combination strategy, highlighting the need to decipher and overcome resistance.Objective We sought to investigate the mechanisms by which chemotherapy augments the responses to immune checkpoint blockade and elucidate the factors contributing to persistent resistance in non-responding patients.Design We designed a systematic investigation involving longitudinal sampling of ESCC tissues both from patients treated with chemotherapy plus anti-PD-1 and anti-PD-1 monotherapy. The tumour microenvironment (TME) was then comprehensively characterised using single-cell transcriptomics, T cell receptor repertoire analysis, multiplex immunohistochemistry and murine models.Results We demonstrated that combination therapy exerted superior antitumour efficacy by mitigating immune checkpoint engagements (TIGIT-NECTIN2 and NECTIN1-CD96) between epithelial-stress tumour cells and CD8 + T cells, thereby preventing T cells from exhaustion and boosting vitality. In non-responders, we identified a subset of tumour cells with high SLC1A3 expression, which localised at the tumour boundary and interacted with COL1A1+ myofibroblastic cancer-associated fibroblasts, inducing an extracellular matrix-enriched TME that hindered the infiltration of CD8+ T cells. Inhibiting SLC1A3 significantly enhanced the efficacy of chemotherapy plus anti-PD-1, underscoring its potential as a therapeutic target.Conclusion This study elucidates the synergistic mechanisms and identifies key resistance pathways underlying chemo-immunotherapy combinations in patients with ESCC, providing a scientific basis for refining future combination therapeutic regimens.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China"
      ],
      "name": "Shujing Xiang"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China"
      ],
      "name": "Yanxing Chen"
    },
    {
      "affiliations": [
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China",
        "Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China"
      ],
      "name": "Chaoye Wang"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China"
      ],
      "name": "Min Wang"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China"
      ],
      "name": "Ye He"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China"
      ],
      "name": "Zhichao Liu"
    },
    {
      "affiliations": [
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China",
        "Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China"
      ],
      "name": "Jin-Ling Zhang"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Lu-Ping Yang"
    },
    {
      "affiliations": [
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China",
        "Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China"
      ],
      "name": "Yun-Fu Wei"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Qi-Nian Wu"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China"
      ],
      "name": "Zi-Xian Wang"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Shao-Yan Xi"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China"
      ],
      "name": "Zhigang Li"
    },
    {
      "affiliations": [
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China",
        "Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China"
      ],
      "name": "Qi Zhao"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China"
      ],
      "name": "Rui-Hua Xu"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, Guangdong, China"
      ],
      "name": "Feng Wang"
    }
  ],
  "title": "Alleviated T cell exhaustion and SLC1A3-mediated stroma-remodelling dictate chemoimmunotherapy efficacy in oesophageal squamous cell carcinoma",
  "uid": "23e7e04b-a32f-53ce-b40e-f203ad12aa96"
}