Abstract

Non-Small-Cell Lung Cancer (NSCLC) often responds poorly to immune checkpoint blockade due to its immunosuppressive, “cold” tumor microenvironment. Activating alternative immune effectors may overcome this limitation. Here we identified lung-enriched γδ T cells as a key compartment in NSCLC and developed a lung-targeted lipid nanovaccine to activate them in situ. Analysis of patient transcriptomic data sets reveals that γδ T cell and CD1d signatures are associated with improved patient survival in NSCLC. Using this insight, we engineered α-galactosylceramide (α-GalCer) and poly(I:C)-loaded lipid nanoparticles that preferentially accumulated in the lung after intravenous administration. In orthotopic NSCLC models, the nanovaccine activated γδ T cells, enhanced functional CD8+ T cell infiltration, remodeled the immunosuppressive tumor microenvironment, and significantly prolonged survival. Depletion of γδ T cells abolished therapeutic benefit, demonstrating that γδ T cells represented the important effector population for this strategy. Furthermore, splenectomy attenuated vaccine efficacy, suggesting a contribution of systemic immune crosstalk to vaccine efficacy. Together, these findings establish a γδ T cell-centered lung-targeted immunotherapy strategy for treating immune-resistant NSCLC.