Hydrogen Therapy Reverses Cancer-Associated Fibroblasts Phenotypes and Remodels Stromal Microenvironment to Stimulate Systematic Anti-Tumor Immunity

Xiaoyan Meng; Zhonglong Liu; Liang Deng; Yangzi Yang; Yingchun Zhu; Xiaoying Sun; Yongqiang Hao; Yue He; Jingke Fu

doi:10.1002/advs.202401269

Hydrogen Therapy Reverses Cancer-Associated Fibroblasts Phenotypes and Remodels Stromal Microenvironment to Stimulate Systematic Anti-Tumor Immunity

Adv Sci (Weinh). 2024 May 17:e2401269. doi: 10.1002/advs.202401269. Online ahead of print.

Authors

Xiaoyan Meng^{1

2}, Zhonglong Liu^{1

2}, Liang Deng^{3

4}, Yangzi Yang⁵, Yingchun Zhu⁶, Xiaoying Sun⁷, Yongqiang Hao^{3

4}, Yue He^{1

2}, Jingke Fu^{3

4}

Affiliations

¹ Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China.
² College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, P. R. China.
³ Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China.
⁴ Clinical and Translational Research Center for 3D Printing Technology, Shanghai Engineering Research Center of Innovative Orthopaedic Instruments and Personalized Medicine, Shanghai, 200011, P. R. China.
⁵ Department of Orthopedic Surgery, Spine Center, Changzheng Hospital, Navy Medical University, No. 415 Fengyang Road, Shanghai, 200003, P. R. China.
⁶ Key Laboratory of Inorganic Coating Materials, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China.
⁷ College of Sciences, Shanghai University, Shanghai, 200444, P. R. China.

PMID: 38757665
DOI: 10.1002/advs.202401269

Abstract

Tumor microenvironment (TME) plays an important role in the tumor progression. Among TME components, cancer-associated fibroblasts (CAFs) show multiple tumor-promoting effects and can induce tumor immune evasion and drug-resistance. Regulating CAFs can be a potential strategy to augment systemic anti-tumor immunity. Here, the study observes that hydrogen treatment can alleviate intracellular reactive oxygen species of CAFs and reshape CAFs' tumor-promoting and immune-suppressive phenotypes. Accordingly, a controllable and TME-responsive hydrogen therapy based on a CaCO₃ nanoparticles-coated magnesium system (Mg-CaCO₃) is developed. The hydrogen therapy by Mg-CaCO₃ can not only directly kill tumor cells, but also inhibit pro-tumor and immune suppressive factors in CAFs, and thus augment immune activities of CD4⁺ T cells. As implanted in situ, Mg-CaCO₃ can significantly suppress tumor growth, turn the "cold" primary tumor into "hot", and stimulate systematic anti-tumor immunity, which is confirmed by the bilateral tumor transplantation models of "cold tumor" (4T1 cells) and "hot tumor" (MC38 cells). This hydrogen therapy system reverses immune suppressive phenotypes of CAFs, thus providing a systematic anti-tumor immune stimulating strategy by remodeling tumor stromal microenvironment.

Keywords: cancer‐associated fibroblasts; hydrogen therapy; immunotherapy; tumor microenvironment.

Abstract

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