Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development

• Published in: Signal transduction and targeted therapy 2021-09, Vol.6 (1), p.330-330, Article 330
• Main Authors: Li, Ming, Hao, Bingjie, Zhang, Menghuan, Reiter, Russel J., Lin, Shumeng, Zheng, Tiansheng, Chen, Xiangyun, Ren, Yanbei, Yue, Liduo, Abay, Baigenzhin, Chen, Guojie, Xu, Xiao, Shi, Yufeng, Fan, Lihong
• Format: Article
• Language: English
• Subjects: 631/67/1612; 692/699/67/1612; Acidification; Adult; Aged; Aged, 80 and over; Animals; Antitumor activity; Cancer Research; Cell Biology; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Combined Modality Therapy; Female; Hedgehog Proteins - genetics; Heterografts; Humans; Hypoxia; Internal Medicine; Kaplan-Meier Estimate; Killer Cells, Natural - drug effects; Killer Cells, Natural - radiation effects; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Lung nodules; Male; Malignancy; MAP kinase; Medicine; Medicine & Public Health; Melatonin; Melatonin - administration & dosage; Metabolism; Mice; Middle Aged; Mitogen-Activated Protein Kinase Kinases - genetics; Multiple Pulmonary Nodules - drug therapy; Multiple Pulmonary Nodules - genetics; Multiple Pulmonary Nodules - pathology; Multiple Pulmonary Nodules - radiotherapy; Neoplasm, Residual - drug therapy; Neoplasm, Residual - genetics; Neoplasm, Residual - pathology; Neoplasm, Residual - radiotherapy; NF-kappa B - genetics; NF-κB protein; Oncology; Oxidative phosphorylation; Pathology; Phosphorylation; Progression-Free Survival; Proteomics; Radiofrequency ablation; Radiofrequency Ablation - adverse effects; Respiratory function; Treatment Outcome; Tumor microenvironment; Tumors; Wnt protein; Wnt Signaling Pathway - drug effects; Wnt Signaling Pathway - radiation effects
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-021-00745-7

Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn , identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931 .