Single-cell and spatial transcriptomics reveals an anti-tumor neutrophil subgroup in microwave thermochemotherapy-treated lip cancer.

Journal: International journal of oral science
Published Date: May 13, 2025

Abstract

Microwave thermochemotherapy (MTC) has been applied to treat lip squamous cell carcinoma (LSCC), but a deeper understanding of its therapeutic mechanisms and molecular biology is needed. To address this, we used single-cell transcriptomics (scRNA-seq) and spatial transcriptomics (ST) to highlight the pivotal role of tumor-associated neutrophils (TANs) among tumor-infiltrating immune cells and their therapeutic response to MTC. MNDA TANs with anti-tumor activity (N1-phenotype) are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion, and these TANs are characterized by enhanced cytotoxicity, ameliorated hypoxia, and upregulated IL1B, activating T&NK cells and fibroblasts via IL1B-IL1R. In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC, fibroblasts accumulated in the tumor front (TF) can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs (pro-tumor phenotype) via CXCL12-CXCR4, which results in the aggregation of N1-TANs and extracellular matrix (ECM) deposition. In addition, we construct an N1-TANs marker, MX2, which positively correlates with better prognosis in LSCC patients, and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin (H&E)-stained images so as to conveniently guide decision making in clinical practice. Collectively, our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.

Authors

  • Bingjun Chen
    State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Huayang Fan
    State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Xin Pang
    Biomedical Group, Campus Gasthuisberg, KU Leuven, 3000, Leuven, Belgium.
  • Zeliang Shen
    State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Rui Gao
    School of Control Science and Engineering, Shandong University, Jinan, China.
  • Haofan Wang
    Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China (X.W., W.Y., Y.G., Y.G., H.W., Y.Z., D.P., X.G., W.C.).
  • Zhenwei Yu
    College of Mechanical and Electronic Engineering, Shandong Agricultural University, Tai'an 271018, China; Shandong Provincial Engineering Laboratory of Agricultural Equipment Intelligence, Shandong Provincial Key Laboratory of Horticultural Machineries and Equipment, Tai'an 271018, China.
  • Tianjiao Li
    School of Management Science and Engineering, Shanxi University of Finance and Economics, Taiyuan 030006, China.
  • Mao Li
    Machine Intelligence Laboratory, College of Computer Science, Sichuan University, Chengdu 610065, P. R. China.
  • Yaling Tang
  • Xinhua Liang
    State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China. lxh88866@scu.edu.cn.

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