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

Li M. Hao B. Zhang M. Reiter R.J. Lin S. Zheng T. Chen X. Ren Y. Yue L. Abay B. Chen G. Xu X. Shi Y. Fan L.
December 2021 Springer Nature

Signal Transduction and Targeted Therapy
2021 #6 Issue 1

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.

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Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, China
Clinical Center For Brain And Spinal Cord Research, Tongji University, Shanghai, China
Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, United States
National Scientific Medical Research Center, Astana, Kazakhstan
State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

Department of Respiratory Medicine
Institute of Energy Metabolism and Health
Tongji University Cancer Center
Clinical Center For Brain And Spinal Cord Research
Department of Cell Systems and Anatomy
National Scientific Medical Research Center
State Key Laboratory of Molecular Biology

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