Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic-Reticulum-Targeted Therapy: Left or Right?

Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of autophagy better suits ER-targeting therapy remains controversial. Here, a targeted nanosystem is constructed, which efficiently escorts anticancer therapeutics into the ER, triggering substantial ER stress and autophagy. Concurrently, an autophagy enhancer or inhibitor is combined into the same nanoparticle, and their impacts on ER-related activities are compared. In the orthotopic breast cancer mouse model, the autophagy enhancer increases the antimetastasis effect of ER-targeting therapy and suppresses over 90% of cancer metastasis, while the autophagy inhibitor has a bare effect. Mechanism studies reveal that further enhancing autophagy accelerates central protein snail family transcriptional repressor 1 (SNAI1) degradation, suppressing downstream epithelial-mesenchymal transition, while inhibiting autophagy does the opposite. With the same trend, ER-targeting therapy combined with an autophagy enhancer provokes stronger immune response and tumor inhibition than the autophagy inhibitor. Mechanism studies reveal that the autophagy enhancer elevates Ca2+ release from the ER and functions as a cascade amplifier of ER dysfunction, which accelerates Ca2+ release, resulting in immunogenic cell death (ICD) induction and eventually triggering immune responses. Together, ER-targeting therapy benefits from the autophagy-enhancing strategy more than the autophagy-inhibiting strategy for antitumor and antimetastasis treatment.

Automated summary

In this study, a targeted nanosystem was developed to efficiently deliver anticancer therapeutics into the endoplasmic reticulum (ER), triggering ER stress and autophagy. The effects of an autophagy enhancer and inhibitor on ER-related activities were compared, and it was found that the autophagy enhancer increased the antimetastasis effect of ER-targeting therapy, while the autophagy inhibitor had little effect. Mechanistic studies revealed that the autophagy enhancer accelerated the degradation of the protein SNAI1 and suppressed epithelial-mesenchymal transition, while inhibiting autophagy had the opposite effect. Furthermore, ER-targeting therapy combined with the autophagy enhancer induced a stronger immune response and tumor inhibition compared to the autophagy inhibitor. Mechanistic studies showed that the autophagy enhancer increased calcium release from the ER, leading to immunogenic cell death and triggering immune responses. Overall, the autophagy-enhancing strategy is more beneficial for ER-targeting therapy in antitumor and antimetastasis treatment.