Pyroptosis‐Inducing Engineered Microparticles for Cancer Immunotherapy

ABSTRACT Pyroptosis, a form of immunogenic cell death, can remodel the immunosuppressive tumor microenvironment; however, its clinical translation is challenged by difficulties in targeted induction and biosafety concerns. In this study we discovered that geldanamycin (GA) can interacts specifically with arginine 207 (R207) in caspase‑3, and efficiently cleaved caspase‐3, significantly inducing high‐efficiency pyroptosis. Although high‐dose GA promoted pyroptosis and antitumor immunity, physiological toxicity and the induction of resistance mediated by immune checkpoints including PD‐L1 and CD47 limited therapeutic efficacy. To address this, we developed biomimetic dual‐targeting microparticles(MPs)functionalized with anti‐PD‐L1 and anti‐SIRPα nanobodies. This strategy synergized targeted pyroptosis induction with dual immune checkpoint blockade, achieving complete tumor regression, reduced physiological toxicity, and induced a potent effector immune response in murine cancer models, presenting a promising combinatorial approach for lung cancer immunotherapy.