Supramolecular self-assembled nanomedicine targeting fatty acid metabolism to potentiate ferroptosis-enhanced photoimmunotherapy in triple-negative breast cancer

Triple-negative breast cancer (TNBC) presents a serious therapeutic challenge, largely owing to its metabolic adaptability and the immunosuppressive nature of its tumor microenvironment (TME). Photodynamic therapy (PDT) can cause oxidative injury and induce immunogenic cell death (ICD); however, its antitumor activity is often limited by inadequate reactive oxygen species (ROS) accumulation and weak immune activation. To address these barriers, a supramolecular self-assembled nanoplatform, termed OC@cRGD, was constructed through the co-assembly of the fatty acid synthase (FASN) inhibitor orlistat and the photosensitizer chlorin e6 (Ce6), followed by cyclic RGD (cRGD) modification to support integrin-mediated tumor targeting. This self-assembled design allows high drug loading and links metabolic interference with redox stress in a single nanoscale formulation. At the mechanistic level, orlistat disturbs lipid homeostasis and reduces the saturated fatty acid–based protection that helps TNBC cells resist membrane peroxidation. In parallel, light-activated PDT delivers a spatially restricted oxidative burst. After laser irradiation, these two processes act together to drive extensive iron-dependent lipid peroxidation, along with reduced GPX4 and FASN expression, thereby increasing cellular susceptibility to ferroptosis. This ferroptosis-reinforced PDT further induces pronounced ICD. In 4T1 tumor-bearing mice, OC@cRGD combined with laser irradiation inhibited tumor growth and reshaped the immune microenvironment, as reflected by dendritic cell maturation, M1-like macrophage polarization, and increased CD8 + T-cell infiltration. Overall, this study combines metabolic intervention with photoimmunotherapy and offers a metabolism-guided strategy for the development of self-assembled nanotherapeutics.