Modulating autophagy in the tumor microenvironment with a salinomycin-loaded liposome hybrid nanovesicle system for tumor immunotherapy

Salinomycin (SAL) is a potent polyether antibiotic with antitumor potential, but has limited clinical application due to its poor water solubility and unresolved immune stimulatory properties. This study introduces a SAL- loaded liposome hybrid nanovesicle (SAL@LINV) via the fusion of artificial SAL-loaded liposomes with tumor- derived nanovesicles (TNV) via a continuous extrusion technique to address these challenges. SAL@LINV not only significantly enhances the solubility and bioavailability of SAL but also actively affects the tumor micro- environment (TME), modulating autophagy and enhancing the immune response. The fusion of TNV into SAL@LINV confers the targeting specificity of SAL@LINV to tumors and finely tunes cellular autophagy, inducing immunogenic cell death (ICD) in tumors, increasing antigen presentation by DCs, and modulating macrophage polarization to the M1 type. In vivo studies utilizing subcutaneously implanted MC38 and B16/F10 tumor models have demonstrated the superior antitumor efficacy and immune-activating capabilities of SAL@LINV. Furthermore, single-cell RNA sequencing revealed the molecular mechanisms by which SAL@LINV, an immunotherapeutic agent, reshaped the TME and promoted an antitumor immune response. This integrated "three-in-one" approach addresses the multifaceted challenges of the TME through nanoparticle-based autophagy modulation, thereby reinforcing the immune system's tumor-combining capabilities.