Authors
Zeyu Yang, Liyan Li, Zepeng He, Haolin Chen, Zhenfu Wen, Zhihui Zhang, Hong Liu, Lixin Liu, Yongming Chen
Published in
ACS nano. Jul 07, 2026. Epub Jul 07, 2026.
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.
PMID:
42413111
Bibliographic data and abstract were imported from PubMed on 08 Jul 2026.
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