Multifunctional immunomodulator with cascade catalytic activities to reprogram endoplasmic reticulum stress-mediated immunosuppression for enhancing anti-tumor immunotherapy.

Abstract

Endoplasmic reticulum (ER) stress has been identified as a critical regulator of cholesterol metabolism and tumor-derived extracellular vesicles (tEVs) secretion in tumor cells, which significantly influences TME composition and impairs anti-tumor immune responses. Here, we develop a multifunctional immunomodulator (CPMR) that simultaneously targets cholesterol metabolism and tEVs secretion, thereby reprogramming the ER stress-mediated immunosuppression and enhancing anti-tumor immunotherapy. CPMR is constructed by co-loading cholesterol oxidase (ChOx) and Rab27a-shRNA plasmid into a copper-based metal-organic framework (MOF-199) coated with DSPE-PEG-RGD. In 4T1 tumor cells, CPMR demonstrates favorable glutathione peroxidase-mimicking, ChOx and peroxidase-like activities, initiating cascade catalytic reactions that disrupt the intracellular redox and metabolic homeostasis, further triggering acute ER stress. Simultaneously, silencing of Rab27a effectively inhibits tEVs-mediated cholesterol efflux. The resulting intracellular cholesterol accumulation serves as a substrate for subsequent ChOx-mediated oxidative reactions, forming a positive feedback loop that amplifies oxidative stress. These synergistic effects ultimately induce immunogenic cell death. Notably, the reduction in extracellular levels of cholesterol and tEVs effectively mitigates the ER stress-mediated immunosuppression, thereby potentiating immune responses. This study offers a promising strategy to harness and mitigate the subsequent effects of ER stress for the advancement of anti-tumor immunotherapy.