Mechanoregulatory Cholesterol Oxidase‐Functionalized Nanoscale Metal–Organic Framework Stimulates Pyroptosis and Reinvigorates T Cells

Abstract 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.