A novel photosensitizer-based photodynamic therapy reprograms the Kynurenine-AhR axis to boost antitumor immunity in breast cancer.

Photodynamic therapy (PDT) has emerged as a promising local treatment for breast cancer, with emerging evidence highlighting its potential to modulate the immune response. However, its effects on tumor microenvironment (TME) metabolism remain poorly understood. In this study, we introduce a novel photosensitizer, DTP, which efficiently generates reactive oxygen species and induces apoptosis in breast cancer cells in vitro. In vivo, DTP preferentially accumulates in tumors, significantly inhibiting tumor growth and reducing Ki-67 expression upon 650 nm irradiation. Untargeted metabolomics revealed significant alterations in the tryptophan metabolism pathway following DTP-PDT. Further targeted metabolomic analysis identified a specific reduction in kynurenine (Kyn), an immunosuppressive metabolite, within the tumor. Mechanistically, DTP-PDT reduced indoleamine 2,3-dioxygenase 1 (IDO1)-dependent Kyn production, diminished AhR nuclear localization and decreased AhR transcriptional activity in tumor-infiltrating T cells. This metabolic reprogramming alleviated the immunosuppressive TME, as evidenced by increased infiltration of CD8+ T cells and a reduction in regulatory T cells. Notably, exogenous Kyn partially restored the Kyn-AhR axis and attenuated the immune remodeling induced by DTP-PDT. Building on these immune-activating effects, we combined DTP-PDT with PD-L1 blockade, which significantly suppressed pulmonary metastasis and enhanced central memory T-cell generation, resulting in durable systemic antitumor immunity.