Tumor-Associated Macrophage-Mediated Delivery of Nano-photosensitizer Enables Light-Induced Metabolic Programming for Immuno-Photodynamic Therapy

Fully unlocking the therapeutic potential of tumor-associated macrophages (TAMs) for effective cancer treatment requires both precise targeting and functional reprogramming, which remains a formidable challenge. In this work, we achieve light-stimulated TAM polarization for improved immuno-photodynamic (PDT) therapy in a murine breast cancer model using a positively-charged dextran nano-photosensitizer (p-Dex PS), and unveil the underlying mechanism. The p-Dex PS engulfed by TAMs could be efficiently transported to tumor cells as verified by using both the co-culture of tumoral and macrophagic cells in vitro and the 4T1 tumor model in vivo, supporting TAMs' role as depots for photosensitizers delivery within tumors. Further metabolomics analysis reveals that sublethal light irradiation induces metabolic reprogramming of TAMs that targeted by p-Dex PS, which greatly contributes to the TAM polarization as well as the antitumor immunity. This p-Dex PS significantly improves the bioavailability and immune stimulation of photosensitizer through targeting the TAMs, providing a practicable and facile PDT strategy to combat the breast cancer.