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

Abstract 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.