Reprogramming Disulfide Reduction in Endoplasmic Reticulum Uncouples Immune Evasion of Pancreatic Cancer.

Abstract

The modulation of immune checkpoint activity exerts profound impacts on tumor immunotherapy. However, the interfere of mature immune checkpoints encounter efficacy challenges in solid tumors, which underlies a critical barrier in clinical translation of multiple potential targets. Herein, we propose a biochemical immune modulation strategy for immunosuppression reversal by blocking the mature of CD47 within the endoplasmic reticulum (ER). Clinically used radionuclides iodine-131 (¹³¹I) is reengineered to encapsulate within microporous barium titanate nanoparticles, forming an immunoactive nanomodulator. Leveraging polarized and collisional relaxation, the electrons emitted from ¹³¹I mediate continuous disulfide bond reduction, blocking CD47 folding and surface translocation, resulting in a 93.6% reduction in CD47 expression. Together with the remarkable increase of tumor antigen presentation induced by ER reductive stress in pancreatic tumor-bearing mice, we realize a 93% tumor inhibition and a 3-fold prolongation of survival. This work underscores the role of organellar biochemistry in reshaping immunosuppression for tumor immunotherapy.