Rationally Integrated Precise ER-Targeted and Oxygen-Compensated Photodynamic Immunostimulant for Immunogenicity-Boosted Tumor Therapy

Notwithstanding that immunotherapy has made eminent clinical breakthroughs, activating the immunogenicity and breaking the immunosuppressive tumor microenvironment (ITME) remains tempting yet challenging. Herein, a customized-designed immunostimulant is engineered for attenuating ITME and eliciting an immune response to address this challenge head-on. This immunostimulant is equipped with dual silica layers coated upconversion nanoparticles (UCNPs) as nanocarriers modified with endoplasmic reticulum (ER)-targeted molecular N-p-Tosylglycine, in which the dense silica for chlorin e6 (Ce6) and the glutathione (GSH)-responsive degradable silica for loading resveratrol (RES) - (UCSMR^ER ). On the one hand, this precise ER-targeted photodynamic therapy (PDT) can generate reactive oxygen species (ROS) in situ under the 980 nm laser irradiation, which not only induced severe cell death directly but also caused intense ER stress-based immunogenic cell death (ICD). On the other hand, tumor hypoxia aggravated by the PDT is alleviated by RES released on-demand, which reduced oxygen consumption by impairing the mitochondrial electron transport chain (ETC). This integrated precise ER-targeted and oxygen-compensated strategy maximized the PDT effect and potentiated ICD-associated immunotherapy, which availed to attenuate ITME, activate tumor immunogenicity, and further magnify the anti-tumor effect. This innovative concept about PDT and immunotherapy sheds light on cancer-related clinical application.