Inhaled Fluorinated Polymer Triggers Pyroptosis for Lung Cancer Immunotherapy.

Lung cancer imposes the highest cancer-related mortality burden worldwide, while its responsiveness to immunotherapy is often constrained by the immunosuppressive pulmonary tumor microenvironment (TME) and tumor adaptations that buffer oxidative stress. Pyroptosis, a highly immunogenic form of programmed cell death that can be activated through mechanisms not strictly dependent on exogenous reactive oxygen species (ROS), offers a promising alternative for immune activation but remains challenging to induce effectively in vivo. Here, we report an inhalable fluorinated polymer nanoplatform (PFAP) that triggers mitochondrial dysfunction to initiate pyroptosis and thereby elicits potent antitumor immunity in the lung. PFAP integrates perfluoroalkyl segments with cationic domains to enhance interactions with mitochondrial membranes, while a detachable polyethylene glycol shell preserves nanoparticle stability during aerosolization and facilitates penetration of pulmonary barriers. Upon exposure to the acidic TME, PFAP restores membrane-disruptive activity, leading to mitochondrial depolarization, Cyto C release, caspase-3 activation, GSDME cleavage, and pyroptosis induction. In orthotopic and metastatic lung cancer models, inhaled PFAP achieves efficient lung delivery, elicits robust antitumor immunity, and suppresses tumor progression without detectable systemic toxicity. This work provides a nanomaterial-based approach for inducing pyroptosis in lung cancer and highlights the potential of inhalable polymer systems for localized cancer immunotherapy.