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

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 Ca²⁺ 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.