Nanoengineered Light-Switchable Micelles for Dual Chemo-Photodynamic Immunotherapy in Esophageal Cancer via Spatiotemporal Control of the Tumor Microenvironment

Immunotherapy has emerged as a promising therapeutic modality for esophageal cancer (EC). Nevertheless, its clinical efficacy is frequently constrained by the overexpression of the vascular endothelial growth factor (VEGF) and the inherently low immunogenicity of EC cells. To address these limitations, we engineered a novel self-assembled nanoplatform utilizing the thin-film dispersion method. This platform comprises a biocompatible PVCL-PVA-PEG triblock copolymer designed for the codelivery of paclitaxel (PTX) and verteporfin (VER). This copolymer demonstrates a relatively low critical micelle concentration (CMC), thereby enhancing its stability and retention within physiological environments─attributes conferring advantages over conventional carriers, such as liposomes or PLGA-based nanoparticles. This study introduces a VER-based delivery system exhibiting a unique photoactivatable dual-function capability. In the absence of photostimulation (light-off state), nonphotoactivated VER acts as a potent Yes-associated protein (YAP) inhibitor, effectively attenuating VEGF-induced angiogenesis. Concurrently, PTX induces immunogenic cell death (ICD), activating antitumor immune responses. Upon photoirradiation (light-on state), VER-mediated photodynamic therapy (PDT) generates cytotoxic reactive oxygen species (ROS), directly eliminating tumor cells and further amplifying ICD. By integrating this spatiotemporally controlled dual-action mechanism of VER with PTX-induced chemotherapy, the nanoplatform significantly enhances the infiltration of tumoricidal immune effector cells. Consequently, this synergistic therapeutic strategy markedly improves the efficacy of chemo-photodynamic immunotherapy, offering a rational and promising treatment approach for esophageal cancer.