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. Alveolar macrophages can contribute to systemic anti-tumor responses. Here the authors describe a cascaded targeted liposomal nanomedicine for generating chimeric antigen receptor-modified alveolar macrophages via intrapulmonary nebulization, promoting anti-tumor immunity in lung cancer models.