Photodynamic therapy (PDT) is a promising cancer treatment method, but its efficacy is often impaired due to tumor hypoxia and limited immune activation. We have developed a multifunctional photosynthesis nanoplatform (PnanoCB), derived from the microcystis vesiculosa strain, aiming to alleviate hypoxia, enhance ROS-mediated tumor cell killing, and activate anti-tumor immunity. The cyanobacteria are restructured into vesicles derived from the protoplast, retaining photosynthetic capabilities and chlorophyll, and functionalized with pH-sensitive pH low insertion peptides (pHLIP) through a cleavable matrix metalloproteinase-2 (MMP-2) anti-PD-L1 peptide to target tumor immunosuppressive checkpoints. After blue light irradiation, PnanoCB efficiently generates oxygen in situ, overcoming hypoxia and significantly enhancing ROS production induced by PDT. Combining PnanoCB with a fasting-like diet (FMD) further improves tumor accumulation and therapeutic efficacy. The combination of PnanoCB, light irradiation, and foot-and-mouth disease achieved the strongest tumor suppression in the 4T1 breast cancer model and effectively prevented tumor recurrence in re-challenge models, with no significant toxicity to major organs. Overall, PnanoCB significantly alleviates hypoxia, promotes immunogenic cell death, and activates robust dendritic cells (DC) maturation by stimulating the interferon gene (STING) pathway. This study demonstrates a strategy combining photosynthesis oxygen generation, photodynamic immunotherapy, and metabolic intervention to reshape the tumor microenvironment and induce robust systemic anti-tumor immunity. This research was published in Advanced Materials under the title "Photosynthetic Nanobacteria Drive Metabolic-Immune Synergy for Hypoxia-Resistant Cancer Therapy".
Reference Information:
DOI: 10.1002/adma.72834