癌细胞会改变其细胞膜的机械张力。调节细胞膜张力的新干预手段可能成为癌症治疗的潜在策略。本文报告了胆固醇氧化酶（COD）通过体外胆固醇耗竭增加细胞膜张力，以及设计一种COD功能化的纳米金属有机框架Hf-TBP/COD，用于体内胆固醇耗竭和肿瘤机械调控。发现COD能够耗竭胆固醇并破坏脂质双层的机械特性，从而导致细胞增殖、迁移和对氧化应激的耐受性下降。Hf-TBP/COD增加了癌细胞的质膜机械张力和渗透脆性，引发钙离子流入，抑制细胞迁移，提高促效性半胱氨酸-1介导的火凤凰细胞死亡能力，降低氧化应激的耐受性。在肿瘤微环境中，Hf-TBP/COD降调多个免疫抑制核查点，激活T细胞并增强T细胞浸润。相较于Hf-TBP，Hf-TBP/COD在皮下三阴性乳腺癌模型和结肠癌模型中，提高了抗肿瘤免疫应答和肿瘤生长抑制效果，分别从54.3%和79.8%增至91.7%和95%。© 2023 The Authors. Small published by Wiley-VCH GmbH.

Cancer cells alter mechanical tension in their cell membranes. New interventions to regulate cell membrane tension present a potential strategy for cancer therapy. Herein, the increase of cell membrane tension by cholesterol oxidase (COD) via cholesterol depletion in vitro and the design of a COD-functionalized nanoscale metal-organic framework, Hf-TBP/COD, for cholesterol depletion and mechanoregulation of tumors in vivo, are reported. COD is found to deplete cholesterol and disrupt the mechanical properties of lipid bilayers, leading to decreased cell proliferation, migration, and tolerance to oxidative stress. Hf-TBP/COD increases mechanical tension of plasma membranes and osmotic fragility of cancer cells, which induces influx of calcium ions, inhibits cell migration, increases rupturing propensity for effective caspase-1 mediated pyroptosis, and decreases tolerance to oxidative stress. In the tumor microenvironment, Hf-TBP/COD downregulates multiple immunosuppressive checkpoints to reinvigorate T cells and enhance T cell infiltration. Compared to Hf-TBP, Hf-TBP/COD improves anti-tumor immune response and tumor growth inhibition from 54.3% and 79.8% to 91.7% and 95% in a subcutaneous triple-negative breast cancer model and a colon cancer model, respectively.© 2023 The Authors. Small published by Wiley-VCH GmbH.