In situ reprogramming of CAR-alveolar macrophages via liposomal nanomedicine for lung cancer immunotherapy.

Immunotherapy has revolutionized lung cancer treatment; however, response rates remain suboptimal. Alveolar macrophages (AMs) within the tumor microenvironment contribute to immunotherapy resistance by inhibiting T cell function through metabolic exhaustion, as well by promoting tumor progression via a pro-tumor M2-like phenotype. Here, we describe a precision-engineered, cascade-targeted liposomal nanomedicine (pCAR-P3/LNP) that enables in situ reprogramming of AMs via a multi-step targeting strategy-including lung accumulation via intrapulmonary nebulization, active cellular targeting, and promoter-driven activation-to generate functionally optimized chimeric antigen receptor-expressing AMs (CAR-AMs). The CAR-AMs mediate synergistic antitumor efficacy through three integrated mechanisms: targeted phagocytosis of lung cancer cells, enhanced antigen presentation, and M1-like repolarization. Furthermore, CAR-AM-induced immune activation and memory potentiate the efficacy of immune checkpoint inhibitors and suppress metastatic progression in lung cancer models in female mice. This nanomedicine-based cell reprogramming strategy provides an approach to overcome immunosuppressive barriers in lung cancer immunotherapy and exemplifies the convergence of nanotechnology with immunology for enhanced therapeutic outcomes.