氧化还原稳态的破坏深刻影响细胞的代谢和活动。虽然氧化应激在癌症治疗中得到了广泛的研究，但还原应激的研究仍处于起步阶段。分子氢 (H2) 是一种众所周知的抗氧化剂，由于其强大的抗氧化特性，具有诱导还原应激的巨大潜力，使其成为癌症治疗的有希望的候选者。然而，开发体内可持续的氢气输送系统仍然是一个重大挑战。在此，我们通过设计一种基于凝胶的微胶囊来设计一个微型工厂，该微胶囊封装了产气肠杆菌，又名益生菌生物氢微胶囊（PBMC），从而能够在肿瘤微环境中持续产生氢气。值得注意的是，PBMC 有效抑制了八种肿瘤细胞系以及耐药癌细胞的增殖。 PBMC 中延长的 H2 释放诱导了还原应激，4T1 细胞中 GSH/GSSG 比率显着增加证明了这一点。此外，PBMCs 在乳腺癌、黑色素瘤和肝癌模型中显示出显着的抗肿瘤作用。 PI3K-AKT 通路的抑制和 MAPK 通路的激活被确定为诱导肿瘤细胞周期停滞和凋亡的关键机制。 PBMC 还表现出与化疗药物组合的协同效应，从而有效抑制浸润前癌的生长和通常相关的肺转移。总的来说，我们的研究引入了一种创新策略，通过原位生成 H2 来操纵肿瘤微环境中的还原应激，从而增强肿瘤的脆弱性。版权所有 © 2024 Elsevier Ltd. 保留所有权利。

Disruption of redox homeostasis profoundly affects cellular metabolism and activities. While oxidative stress is extensively studied in cancer therapies, research on reductive stress remains in its infancy. Molecular hydrogen (H2), a well-known antioxidant, holds significant potential to induce reductive stress due to its strong antioxidative properties, making it a promising candidate for cancer therapy. However, it remains a major challenge to develop a sustainable H2 delivery system in vivo. Herein, we designed a micro-factory by engineering a gel-based microcapsule that encapsulates Enterobacter aerogenes, a.k.a. probiotic biohydrogen microcapsules (PBMCs), enabling the sustained H2 generation within tumor microenvironment. Notably, PBMCs effectively suppressed the proliferation of eight tumor cell lines as well as drug-resistant cancer cells. The prolonged H2 release from PBMCs induced reductive stress, as evidenced by a significant increase in the GSH/GSSG ratio in 4T1 cells. Moreover, PBMCs displayed significant antitumor effects in breast, melanoma and liver cancer models. The inhibition of PI3K-AKT pathway and the activation of MAPK pathway were identified as key mechanisms responsible for inducing tumor cell cycle arrest and apoptosis. The PBMCs also exhibited synergistic effects in combination with chemotherapeutics, resulting in robust inhibitions of preinvasive carcinoma growth and commonly associated pulmonary metastasis. Overall, our study introduces an innovative strategy to manipulate reductive stress in the tumor microenvironment through in situ H2 generation, thereby enhancing tumor vulnerability.Copyright © 2024 Elsevier Ltd. All rights reserved.