Acidic-responsive nano liposomes potentiate in situ dual immunotherapy on lung cancer by codelivering antagonistic peptide and agonist.

Current immunotherapies represent a highly promising approach for the treatment of lung cancer. However, their clinical efficacy is often constrained by T cell exhaustion, antibody resistance, and poor tumor penetration, highlighting an urgent need for innovative therapeutic strategies. In this study, we developed an acidic-responsive liposome delivery nanocarrier (PEOz-liposome) for the co-delivery of a programmed cell death ligand 1 (PD-L1)-targeting antagonistic peptide and a Toll-like receptor 7/8 (TLR7/8) agonist. The resulting formulation, designated DRPL (DPPA+R848@PEOz-liposome), demonstrated TME weakly acid-dependent drug release, with cumulative release at pH 6.4 approximately threefold higher than that at physiological pH 7.4. DRPL effectively activated cytotoxic T lymphocytes, reprogrammed tumor-associated macrophages toward M1 phenotype, and promoted dendritic cells maturation. DRPL significantly enhanced tumor accumulation, markedly suppressed primary tumor growth, and remodeled the tumor microenvironment from an immunosuppressive to an immunoactivated state in lung tumor-bearing mice. Critically, DRPL elicited durable, antigen-specific immune memory, as evidenced by complete resistance to tumor rechallenge in cured mice. In summary, the acid-responsive liposomal platform for PD-L1 antagonistic peptide and TLR7/8 agonist codelivery, exhibited significant potential for the immunotherapy of lung cancer via ternary effects, offering a promising ternary therapeutic strategy for lung cancer.