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...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.展开更多
基金supported by National Natural Science Foundation of China grants(Nos.82173326 and 82473058)Key Research and Development Project of Sichuan Province(Nos.2024YFFK0374 and 2024YFFK0198)Interdisciplinary Innovation Project of West China College of Stomatology,Sichuan University(RD-03-202004).
文摘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.
