Redirecting Chemotherapeutics to the Endoplasmic Reticulum Increases Tumor Immunogenicity and Potentiates Anti‐PD‐L1 Therapy

The endoplasmic reticulum (ER) in cancer cells has been considered as a pharmacological target. Still, the effects of a ER-targeted system remain less investigated, due to the fact that most chemo-drugs take actions in the nucleus. Here, it is demonstrated that ER-targeted delivery of doxorubicin (DOX), a typically nucleus-tropic-and-acting agent, attenuates its original effect on cytotoxicity while generating new functions favorable for immune activation. First, a library of DOX derivatives with variable ER-targeting abilities is synthesized. The results reveal that higher ER-targeting efficiency correlates with greater ER stress. As compared with naïve drug, ER-targeted DOX considerably alters the mode of action from nuclear DNA damage-associated cytotoxicity to ER stress-mediated calreticulin exposure. Consequently, ER-targeted DOX decreases cytotoxicity but increases the capability to induce immunogenic cell death (ICD). Therefore, a platform combining naïve and ER-targeted DOX is constructed for in vivo application. Conventional polymer-DOX conjugate inhibits tumor growth by exerting a direct killing effect, and ER-targeted polymer-DOX conjugate suppresses residual tumors by eliciting ICD-associated immunity, together resulting in considerable tumor regression. In addition, simultaneous inhibition of adaptive PD-L1 enrichment (due to negative-feedback to ICD induction) further leads to greater therapeutic outcome. Collectively, ER-targeted therapy can enhance anticancer efficacy by promoting ICD-associated immunotherapy, and potentiating chemotherapy and checkpoint blockade therapy.