{
  "abstract": "Background Neoadjuvant immunochemotherapy (nICT) is increasingly used for resectable non-small cell lung cancer (NSCLC), yet a substantial proportion of patients fail to achieve pathological complete response (pCR). Clinically scalable, minimally invasive biomarkers that predict response and point to actionable resistance mechanisms remain needed.Methods Pretreatment plasma samples collected prior to the first dose were profiled using the Olink proximity extension assay in a Sun Yat-sen University Cancer Center cohort (n=86), randomly split into a training set (n=65) and an internal validation set (n=21). Differentially abundant proteins associated with pCR were identified, and predictive models were developed using logistic regression, random forest, and extreme gradient boosting (XGBoost), followed by internal validation and independent external validation in the Jiangmen Central Hospital cohort (n=46). Survival associations were evaluated by Cox regression. Mechanistic analyses integrated tumor immunohistochemistry/multiplex immunofluorescence, bulk RNA sequencing with immune deconvolution, and functional validation in subcutaneous and orthotopic murine lung cancer models with pharmacologic leukemia inhibitory factor (LIF) blockade.Results Four candidate proteins (LIF, CXCL1, CX3CL1, and NT-3) showed modest single-marker discrimination for pCR (area under the curve (AUC), 0.611–0.673). Multiprotein models improved prediction, with XGBoost achieving the highest performance (training AUC=0.95; internal validation AUC=0.845 (95% CI 0.65 to 1.00); external validation AUC=0.801 (95% CI, 0.57 to 0.93)). SHapley Additive exPlanations analysis identified LIF as the dominant feature negatively associated with pCR probability. Elevated baseline plasma LIF was associated with inferior overall survival (HR=13.003; 95% CI 1.456 to 116.135; p=0.0217) and progression-free survival (HR=3.75; 95% CI 1.362 to 10.327; p=0.0105) after nICT. High LIF tumors exhibited reduced CD8 + T-cell infiltration and suppressed cytotoxic effector programs. In murine models, LIF blockade synergized with immunochemotherapy to enhance antitumor efficacy, restore CD8+ T-cell effector function, and mitigate T-cell exhaustion.Conclusions Baseline plasma proteomics shows promise for predicting pCR to nICT in resectable NSCLC and nominates LIF as a predictive, prognostic, and therapeutic candidate mediator of resistance. These findings warrant prospective validation and further investigation of LIF-targeted combination strategies in the neoadjuvant setting.",
  "authors": [
    {
      "affiliations": [
        "Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China",
        "Lung Cancer Research Center, Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Shoucheng Feng"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China"
      ],
      "name": "Ziqing Feng"
    },
    {
      "affiliations": [
        "Department of Nuclear Medicine, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China"
      ],
      "name": "Songzuo Xie"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China",
        "Lung Cancer Research Center, Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Yuheng Zhou"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China",
        "Lung Cancer Research Center, Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Weizhen Sun"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China",
        "Lung Cancer Research Center, Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Nengqi Lin"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, Jiangmen Central Hospital, Jiangmen, China"
      ],
      "name": "Zhichao Lin"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China",
        "Lung Cancer Research Center, Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Qinglin Wang"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China",
        "Lung Cancer Research Center, Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Zerui Zhao"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China",
        "Lung Cancer Research Center, Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Yaobin Lin"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China",
        "Lung Cancer Research Center, Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Hao Long"
    }
  ],
  "title": "Plasma proteomics predicts pathological complete response and reveals LIF as a potential mediator of resistance to neoadjuvant immunochemotherapy in resectable NSCLC",
  "uid": "7d2937a4-c589-581b-9034-401c1b533c25"
}