A photodynamically activated nanoplatform relieves glucose-driven immunosuppression to potentiate STING immunotherapy in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) carries a poor prognosis due to its high invasiveness, strong tendency toward metastasis and recurrence, and limited treatment options. Metabolic reprogramming, particularly abnormal glucose metabolism, is a hallmark of TNBC. This dysregulated metabolic pattern is closely associated with the establishment of an immunosuppressive tumor microenvironment (TME). We designed a self-assembling nanoparticle, DI/Ce6@STF, integrating photodynamic therapy (PDT), glucose metabolism intervention, and cGAS-STING pathway activation to achieve synergistic antitumor effects. Under 660 nm laser irradiation, DI/Ce6@STF NPs induce immunogenic cell death (ICD) while releasing the STING agonist DIABZI, the GLUT1 inhibitor STF-31, and reactive oxygen species (ROS) causing oxidative damage. STF-31-mediated glucose uptake inhibition not only reduces energy supply but also synergistically enhances tumor response to DIABZI-induced cGAS-STING activation, significantly improving the TME. Collectively, DI/Ce6@STF induces potent ICD, promotes dendritic cell maturation, and enhances intratumoral infiltration of CD8 T cells, thereby reprogramming the immunosuppressive TME. In vivo DI/Ce6@STF nanoparticles demonstrated not only excellent biocompatibility but also highly efficient tumor targeting and enrichment capabilities. They significantly inhibited tumor growth and effectively activated the body's antitumor immune response. By synergistically modulating tumor metabolism and innate immunity, this nanoplatform offers a promising strategy for overcoming therapeutic resistance in TNBC.