Efficiently enhancing ferroptosis-mediated immunosensitization in lung cancer by an inhalable immune activation nanoplatform

Immune checkpoint blockade therapy holds promise for inducing lung cancer regression, but its effectiveness is often limited due to the immunosuppressive tumor microenvironment (ITME). Ferroptosis can remodel the ITME and enhance immunotherapy, but traditional inducers exhibit weak immune modulation due to off-target toxicity and low drug concentrations at the tumor site, resulting in poor efficacy. To address these challenges, we explore an inhalable immune activation nanoplatform, named LMS, designed to enhance ferroptosis-mediated immunosensitization in lung cancer. LMS owns high ferroptosis inducer loading and multienzyme catalytic activity. By nebulization delivery, we demonstrate that LMS can fast and efficiently delivery Statins to lung cancer with minimal systemic toxicity. LMS effectively triggers an oxidative stress storm and lipid peroxidation burst to induce ferroptosis in tumor cells, while leveraging ferroptosis and dendritic cell maturation to synergistically enhance T cell immune responses, thereby reversing ITME. Our nanoplatform achieved efficient tumor suppression in an in-situ lung cancer model, demonstrating the great potential of the inhalable immune activation nanoplatform in ferroptosis-regulated cancer immunotherapy. This work paves a new path for safely and efficiently reversing the ITME in lung cancer, potentially accelerating the development of inhalable immune nanoagonists for clinical applications in cancer immunotherapy.