Breaking Spatiotemporal Barriers of Immunogenic Chemotherapy via an Endoplasmic Reticulum Membrane-Assisted Liposomal Drug Delivery

Immunogenic chemotherapy is a promising approach in cancertreatment,but the number of drugs capable of inducing immunogenic cell deathis limited, and chronic immunogenic exposure can delay antitumor immuneresponse and be counteracted by immunosuppressive factors. In thisstudy, we used single-cell and multilevel analyses to highlight thecritical importance of the first exposure to calreticulin (CRT) ineliciting immunogenicity. We then developed the ERASION (endoplasmicreticulum (ER) membrane to assist (AS) the presentation of intrinsiconco-immunogenicity (ION)) strategy, leveraging the high expressionof functional proteins, including CRT, on the ER membrane. ER membrane-coatedliposome (ER@PLip) was able to target the tumor and immune effectorsand promoted dendritic cell maturation and T cell infiltration. Thisenabled eliciting an immunogenic effect from a nonimmunogenic chemotherapeuticdrug. By utilizing the ER membrane-associated STING protein, ERASIONenabled activating the STING pathway and the generation of adaptiveantitumor immunity. This study presents a potential universal platformfor integrating traditional chemotherapy and therapeutic modalities.

Automated summary

Using single-cell and multilevel analyses, this study emphasizes the critical importance of the first exposure to calreticulin (CRT) in eliciting immunogenicity. The ERASION strategy, utilizing the high expression of functional proteins, including CRT, on the ER membrane, enables the targeting of tumor cells and immune effectors, promoting dendritic cell maturation and T cell infiltration, and eliciting an immunogenic effect from a nonimmunogenic chemotherapeutic drug.