pH-Responsive liposomes co-delivering a membrane-active peptide and the PI3Kγ inhibitor to reconstruct the tumor microenvironment for enhanced antitumor immunotherapy.

Immunotherapy has shown enormous promise for cancer treatment, yet its efficacy is often hindered by the highly immunosuppressive tumor microenvironment (TME). Here, we developed a pH-responsive and cRGD-modified multifunctional liposomal system (FP2@PSLR) to co-deliver an immunogenic cytotoxic peptide (FR) and the PI3Kγ inhibitor IPI549 for coordinated TME remodeling. FR induces immunogenic cell death while exerting direct cytolytic activity, whereas IPI549 promotes macrophage repolarization toward the pro-inflammatory M1-like phenotype, enabling synergistic relief of immune suppression. FP2@PSLR, constructed from acid-sensitive lipids via reverse-phase evaporation, exhibited a uniform size (∼156 nm), high encapsulation efficiencies, excellent physiological stability, and rapid drug release under mildly acidic conditions. In vitro, the liposomes showed good biocompatibility, reduced hemolysis, effective immunogenic cell death induction, dendritic cell activation, and macrophage repolarization. In a 4T1 tumor model, FP2@PSLR demonstrated prolonged circulation, strong αvβ3 integrin-mediated tumor targeting, and clear NIR-II fluorescence for real-time tracking. Treatment resulted in significant TME reprogramming, including enhanced CD8+ T-cell infiltration, increased immune memory formation, and potent antitumor effects without systemic toxicity. These findings highlight FP2@PSLR as a rationally engineered nanoplatform capable of enhancing antitumor immunity through multi-pathway modulation of the immunosuppressive TME.