Co-delivery of endoplasmic reticulum-targeted photosensitizer and Ido-1 inhibitor potentiates immunotherapeutic efficacy in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) generally has a poor response to immunotherapy due to low immunogenicity and an immunosuppressive tumor microenvironment. To address this, a multifunctional nanoparticle, TPI@RPB, was constructed with RGD-PEG-BSA as the carrier for tumor-targeted delivery, while co-loading the self-synthesized endoplasmic reticulum (ER) target photosensitizer TSE-Ppa and Indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-MT. ER-localized reactive oxygen species, generated by TSE-Ppa upon light activation, induce strong immunogenic cell death (ICD). This mechanism facilitates dendritic cell maturation and stimulates the proliferation of CD4+/CD8+ T cells, thereby boosting immunogenicity. Meanwhile, IDO-1 inhibition suppresses tryptophan metabolism-driven immune evasion, thereby reshaping the tumor microenvironment to favor antitumor immunity. In vivo, TPI@RPB not only demonstrates active tumor targeting but also significant antitumor efficacy with a favorable safety profile; specifically, tumor weight reduced to 13.70%, intratumoral CD8+ T-cell infiltration increased 1.92-fold, Treg cells decreased to 51.7%, and splenic effector-memory T cells increased 4.70-fold of control, with no observable systemic toxicity. These results suggest that ER-targeted PDT combined with IDO-1 blockade effectively remodels the tumor microenvironment and elicits durable antitumor immunity in TNBC.