Photosynthetic Nanobacteria Drive Metabolic‐Immune Synergy for Hypoxia‐Resistant Cancer Therapy

Abstract

ABSTRACT Photodynamic therapy (PDT) is a promising cancer treatment, yet its efficacy is often compromised by tumor hypoxia and limited immune activation. Here, we developed a multifunctional photosynthetic nanoplatform (PnanoCB) derived from Microcystis wesenbergii to alleviate hypoxia, enhance reactive oxygen species (ROS)‐mediated tumor cell killing, and activate antitumor immunity. The cyanobacteria were restructured into protoplast‐derived vesicles, retaining photosynthetic capacity and chlorophyll, and functionalized with a Matrix metalloproteinase‐2 (MMP‐2)‐cleavable anti‐PD‐L1 peptide via a pH‐sensitive pH low insertion peptide (pHLIP) linker for tumor‐targeted immune checkpoint blockade. Upon red light irradiation, PnanoCB efficiently generated oxygen in situ, overcoming hypoxia and significantly amplifying PDT‐induced ROS production. Combining PnanoCB with a fasting‐mimicking diet (FMD) further improved tumor accumulation and therapeutic efficacy. The combination of PnanoCB, light irradiation, and FMD achieved the most potent tumor inhibition in a 4T1 breast cancer model and effectively prevented tumor recurrence in a rechallenge model, without detectable toxicity to major organs. Overall, PnanoCB significantly alleviates hypoxia, promotes immunogenic cell death, and triggers robust dendritic cell (DC) maturation through stimulator of interferon genes (STING) pathway activation. This study demonstrates a strategy integrating photosynthetic oxygen generation, photodynamic immunotherapy, and metabolic intervention to remodel the tumor microenvironment and elicit robust systemic antitumor immunity.