No abstract

No 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.

Celastrol may have preventive potential against PCa bone metastasis.

Complete tumor eradication is the ultimate goal of cancer therapy. However, the majority of anticancer drugs cause nonimmunogenic cell death and only exert on-site anticancer activities. The intrinsic genomic instability of cancer allows for the persistence and later expansion of treatment-resistant clones after surviving a sort of Darwinian selection of chemotherapy. Additional incorporation of immunotherapy, which is robust and individualized could be game-changing. Herein, we report a combination strategy that delivers nonimmunogenic cell death inducer Cisplatin to treat primary tumors and converts the tumor cells into vaccines that spurs a long-lasting immune response against residual tumors to prevent tumor recurrence and metastasis. Cisplatin­(IV) prodrug was linked to the N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer (P-Cis) and coadministered with digoxin (Dig), which eventually launched two attacks to cancer cells. First, P-Cis exhibited superior tumor retention and cytotoxicity over free Cisplatin (to inhibit the primary tumor growth). Then, Dig reversed the inability of Cisplatin to trigger calreticulin exposure, and HPMA copolymer-amplified Cisplatin-induced ATP release. These complementary mechanisms induced potent immunogenic cell death that promotes dendritic cell maturation and activates CD8+ T cell responses. In established tumor models, P-Cis + Dig combination completely eradicate tumors with no residual cancer cells remaining. Cancer cells succumbing to P-Cis + Dig could protect syngeneic mice against the subsequent challenge with living cells of the same type and stimulated robust abscopal and antimetastatic effects. Such a strategy might be promising to restore the immunogenicity of nonimmunogenic drugs and generate vaccine-like functions for improved immunochemotherapy.