Radiofrequency radiation reshapes tumor immune microenvironment into antitumor phenotype in pulmonary metastatic melanoma by inducing active transformation of tumor-infiltrating CD8+ T and NK cells

Jia-zheng Jiao1,2, Yang Zhang3,4, Wen-juan Zhang1,2, Min-di He1,2, Meng Meng5, Tao Liu5, Qin-long Ma1,2, Ya Xu3,4, Peng Gao1,2, Chun-hai Chen1,2, Lei Zhang1,2, Hui-feng Pi1,2, Ping Deng1,2, Yong-zhong Wu4, Zhou Zhou6, Zheng-ping Yu1,2, You-cai Deng5, Yong-hui Lu1,2
1 Key Laboratory for Electromagnetic Radiation Medical Protection of Ministry of Education, Army Medical University, Chongqing 400038, China
2 Department of Occupational Health, College of Preventive Medicine, Army Medical University, Chongqing 400038, China
3 Radiation Biology Center, Chongqing University Cancer Hospital, Chongqing 400030, China
4 Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing 400030, China
5 Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China
6 Center for Neurointelligence, School of Medicine, Chongqing University, Chongqing 400030, China
Correspondence to: Zheng-ping Yu:, You-cai Deng:, Yong-hui Lu:,
DOI: 10.1038/s41401-024-01260-5
Received: 25 December 2023
Accepted: 3 March 2024
Advance online: 27 March 2024


Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8+ T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8+ T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8+ T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8+ T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.

Keywords: pulmonary metastatic melanoma; radiofrequency radiation; tumor immune microenvironment; CD8+ T cells; NK cells; cancer immunotherapy

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