Inducing Endoplasmic Reticulum Stress to Expose Immunogens: A DNA Tetrahedron Nanoregulator for Enhanced Immunotherapy

Abstract Immunogenic cell death (ICD) is an important modulation type for stimulating anticancer immune responses and amplifying immunotherapy efficacy. When ICD occurs, endoplasmic reticulum (ER) stress plays a vital role for exposing immunogens. Herein, a functionalized DNA tetrahedron nanoregulator to specifically trigger ER stress for enhancing cancer immunotherapy is designed. The nanoregulator can target ER organelles by binding to the sulfonamide receptor of cancer cells. Then glucose depletion and reactive oxygen species generation cause a strong ER stress response to induce ICD to expose tumor immunogens. Thereafter, the dendritic cell (DC) maturation is promoted, and T cell proliferation and infiltration are stimulated to advance cancer immunotherapy. Combined with immune checkpoint inhibitor (α‐PD‐1), the ER stress triggered nanoregulator exhibits significant suppression for breast cancer and melanoma.