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Despite therapeutic advancements, the prognosis of locally advanced non-small cell lung cancer (LANSCLC), which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes, remains poor. The emergence of immunotherapy with immune checkpoint blockade (ICB) is transforming cancer treatment. However, only a fraction of lung cancer patients benefit from ICB. Significant clinical evidence suggests that the proinflammatory tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression correlate positively with response to the PD-1/PD-L1 blockade. We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized (AeroNP-CDN) for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon (IFN) genes in macrophages and dendritic cells (DCs). Using a mouse model that recapitulates the clinical LANSCLC, we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype, activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+ T cells for adaptive anticancer immunity. Intriguingly, activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors, which, however, set a stage for response to anti-PD-L1 treatment. Indeed, anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice. Importantly, AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity. In conclusion, this study demonstrates a potential nano-immunotherapy strategy for LANSCLC, and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.
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