Stiffening the Soft Tumor: Biosilicification‐Enabled Mechanical Immune Checkpoint Blockade Sono‐Immunotherapy

Abstract Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy by reinvigorating anti‐tumor immunity, while only a small proportion of patients derive benefit from this therapy, with many still facing tumor evasion. As cancer cells exploit cellular softness as a mechanical immune checkpoint to evade immune recognition, pioneering interventions to implement mechanical immune checkpoint blockade (MICB) hold significant promise in enhancing patient outcomes. Here, an innovative strategy is presented to achieve effective MICB sono‐immunotherapy by leveraging the synergistic interplay between in situ biosilicification and sonodynamic therapy (SDT). This approach regulates tumor stiffness to block mechanical immune checkpoints, thereby enhancing T‐cell force and cytotoxicity. The combination of a haematoporphyrin‐silane conjugate, which serves as a sonosensitizer to induce immunogenic tumor cell death, further promotes T‐cell infiltration. More importantly, the in situ biosilicification counteracts the reduction in cortical stiffness caused by SDT, thereby preventing tumor evasion, while also suppressing SDT‐induced exosome secretion to inhibit metastasis. This method offers a novel and versatile alternative to expensive and unstable antibodies, serving as a promising complement to current ICB therapies. It establishes a MICB‐based sono‐immunotherapy approach with potential relevance for future clinical applications.