Piezo‐Electrons Induced Endoplasmic Reticulum Protein Misfolding to Enhance Immune Checkpoint Blockage Cancer Therapy

Abstract The endoplasmic reticulum (ER) is a crucial organelle in eukaryotic cells that regulates protein synthesis, folding, and transport, playing a vital role in maintaining protein homeostasis and functions. Tumor cells evade the immune surveillance and killing of the body by synthesizing immune checkpoint proteins in the ER, thereby inhibiting T cell‐mediated antitumor immune responses and enhancing tumor tolerance, leading to poor efficacy of cancer immunotherapy. Herein, an ultrasound‐triggered piezo‐nanomedicine is designed with endoplasmic reticulum targeting function (BTO v ‐T ER ) to achieve a novel immune checkpoint blockade therapy. Under ultrasound irradiation, BTO v ‐T ER releases piezo‐electrons with reducing properties to disrupt the redox homeostasis of the tumor cell endoplasmic reticulum, thereby inducing protein misfolding and tumor cell apoptosis, which activates antitumor immune response. Meanwhile, due to the protein abnormal folding in the endoplasmic reticulum, the expression of tumor cell immune checkpoint proteins, such as Programmed cell death ligand 1 (PD‐L1) is downregulated, reactivating T cells and promoting antitumor immunotherapy. The strategy of interfering with the processing of various proteins within tumor cells via piezo‐catalysis provides a novel approach for enhancing cancer immunotherapy.