A Peptide Nanoregulator Enriched at the Endoplasmic Reticulum for Boosting Fractionated Radiotherapy‐Mediated Antitumor Immune Response

Abstract Fractionated radiotherapy (FRT), typically delivering low‐dose radiation of 2 Gy per fraction, has been used as the main clinical treatment regimen for various tumors. However, its therapeutic efficacy is severely hindered by inadequate pro‐immunogenic effect and ionizing radiation‐induced immunosuppression. Herein, a peptide nanoregulator (SP ER ‐NO‐Ind) is constructed from self‐assembling peptides that can enrich nitric oxide (NO) at the endoplasmic reticulum (ER) and inhibit indoleamine 2,3‐dioxygenase (IDO) to enhance FRT‐mediated antitumor immunity and reinforce treatment outcomes. SP ER ‐NO‐Ind triggered S ‐nitrosylation of the ryanodine receptor by ER‐specific enrichment of NO, triggering the release of Ca 2+ within ER and induction of robust ER stress. The combination of 2 Gy γ‐radiation with SP ER ‐NO‐Ind induced intense immunogenic cell death (ICD) in ER‐stressed 4T1 cells. Furthermore, this nanoregulator inhibited IDO and decreased kynurenine production, reversing FRT‐induced immunosuppressive effects. The combined application of FRT and SP ER ‐NO‐Ind demonstrated superior efficacy in suppressing breast tumor growth, amplifying abscopal effects, and inhibiting metastasis in mice. The SP ER ‐NO‐Ind treatment achieved a 40% decrease in the total radiation dose while securing equivalent tumor suppression efficacy. Collectively, the work presents a facile approach to augment the efficacy of fractionated radiotherapy for tumors, opening up a new way to enhance the antitumor immune response of radiotherapy.