Importance of the delivery route for the tolerability and efficacy of immunomodulatory agents for lung cancer.

Although immune checkpoint inhibitors have revolutionized lung cancer treatment, their limited efficacy and significant toxicity highlight the need for improved therapeutic strategies. Immunomodulatory agents are known to enhance anti-tumor immune responses. In this study, we investigated how the route of administration affects the tolerability and immunological impact of these immunostimulants. We demonstrate that airway administration of poly I: C, CpG, and an anti-CD137 antibody in healthy mice results in significantly reduced liver toxicity and systemic inflammation compared with intravenous delivery. This was evidenced by lower AST levels, preserved body weight, and a reduced neutrophil-to-lymphocyte ratio. In addition, airway delivery of immunostimulant promoted dose-dependent recruitment of both myeloid and lymphoid cells as compared to intravenous administration. Using a syngeneic orthotopic mouse model of lung carcinoma, we further showed that local airway administration of anti-CD137 antibody resulted in increased pulmonary infiltration of CD4⁺, CD8⁺, and CD4⁺ TRM cells compared with intravenous injection. This enhanced immune infiltration correlated with improved tumor control. Overall, our findings indicate that local administration of immunostimulants enhances pulmonary adaptive immune responses and tumor suppression while limiting systemic toxicity.