Meng Xiaoyan, Liu Zhonglong, Deng Liang, Yang Yangzi, Zhu Yingchun, Sun Xiaoying, Hao Yongqiang, He Yue, Fu Jingke
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.
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.
Adv Sci (Weinh). 2024 Jul;11(28):e2401269. doi: 10.1002/advs.202401269. Epub 2024 May 17.
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 CaCO nanoparticles-coated magnesium system (Mg-CaCO) is developed. The hydrogen therapy by Mg-CaCO 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-CaCO 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.
肿瘤微环境（TME）在肿瘤进展中起重要作用。在TME的组成成分中，癌症相关成纤维细胞（CAFs）表现出多种促肿瘤作用，并可诱导肿瘤免疫逃逸和耐药性。调控CAFs可能是增强全身抗肿瘤免疫力的一种潜在策略。在此，该研究观察到氢气处理可减轻CAFs的细胞内活性氧，并重塑CAFs的促肿瘤和免疫抑制表型。因此，开发了一种基于碳酸钙纳米颗粒包覆镁系统（Mg-CaCO）的可控且对TME有响应的氢疗法。Mg-CaCO介导的氢疗法不仅可以直接杀死肿瘤细胞，还能抑制CAFs中的促肿瘤和免疫抑制因子，从而增强CD4 T细胞的免疫活性。原位植入时，Mg-CaCO可显著抑制肿瘤生长，将“冷”的原发性肿瘤转变为“热”肿瘤，并刺激全身抗肿瘤免疫，这在“冷肿瘤”（4T1细胞）和“热肿瘤”（MC38细胞）的双侧肿瘤移植模型中得到证实。这种氢疗法系统逆转了CAFs的免疫抑制表型，从而通过重塑肿瘤基质微环境提供了一种全身抗肿瘤免疫刺激策略。
