Disruption of ion homeostasis offers potential for antitumor immunity, but its therapeutic effects remain unsatisfactory due to difficulties in achieving robust immunogenicity and unclear molecular mechanisms. This study introduces a tumor-targeted cage-like nanomedicine (CuCa-EB-H), a copper-calcium bimetallic nanocage loaded with proteasome inhibitor bortezomib (BTZ) / copper ion complex elesclomol (ES) and decorated with hyaluronic acid, aiming to unlock the mechanisms that regulate endoplasmic reticulum (ER) stress and mitochondrial dysfunction to induce antitumor immunity.Specifically, BTZ and exogenous Ca²⁺ overload can trigger endoplasmic reticulum (ER) stress, which not only induces the translocation of ER ferritin to the cell surface but also causes a massive release of endogenous Ca²⁺ that is transmitted to the mitochondria, thereby exacerbating mitochondrial Ca²⁺ overload. At the same time, ES mediates the targeted delivery and accumulation of Cu²⁺ in mitochondria, inducing tubular deformation of copper, further aggravating mitochondrial damage and promoting mitochondrial DNA release, thereby activating the cGAS–STING pathway, resulting in ER stress-mediated antitumor immunity.In addition, the effects of copper ions work synergistically with these processes, amplifying the release of damage-associated molecular patterns and demonstrating robust immunogenic effects. The CuCa-EB-H nanomedicine collectively establishes a mutually reinforcing cascade of endoplasmic reticulum stress–mitochondrial dysfunction–STING activation, significantly stimulating dendritic cell maturation, increasing effector T cell infiltration, and reversing the immunosuppressive tumor microenvironment. This study provides mechanistic insights into ion-interference immunotherapy and offers a promising strategy to enhance immune checkpoint therapy.

Original link

Advanced Functional Materials ( IF 19 )

Pub Date : 2025-12-30

DOI: 10.1002/adfm.202527957

Mofan Xiao,  Junmin Qian,  Huichen Zhao,  Xinyu Li,  Chenyang Liu,  Jingjing Fan, Yuhan Li,  Weijun Xu,  Yaping Wang,  Jinlei Wang,  Xiaobing Chen,  Aili Suo