Endoplasmic reticulum-targeted strategies for programmed cell death in cancer therapy: Approaches and prospects

The endoplasmic reticulum (ER) plays a dual role in cancer biology, functioning both to preserve cellular homeostasis and to facilitate pathological progression. Rapidly proliferating cancer cells, which exhibit heightened metabolic activity, frequently experience ER stress that activates the unfolded protein response (UPR), a mechanism that promotes cellular adaptation and survival. However, when ER stress is prolonged or excessive, it can shift the balance toward programmed cell death (PCD), including apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. Given the ER's central role in regulating proteostasis and stress signaling, therapeutically targeting the ER presents a compelling strategy to disrupt cancer cell survival and overcome treatment resistance. Nanomedicine, particularly the use of nanoparticles (NPs) for precise ER targeting, offers a promising platform to modulate ER function and trigger PCD in cancer cells. In this review, we highlight recent advances in the design guidelines of ER-targeted NPs, with a focus on their capacity to engage and activate PCD pathways in cancer cells. We further discuss the current limitations and emerging opportunities in this field, aiming to inform the development of next-generation ER-targeted delivery platforms for enhanced efficacy in cancer treatment.