Reconstructing Tumor Microenvironment Using Photoresponsive Cyanobacteria to Reversal Chemoresistance for Robust Chemotherapy

The solid tumor microenvironment (TME) plays a crucial role in tumor biological behavior, development, and chemoresistance. Herein, a promising strategy is reported to remodel the TME and combat chemoresistance by employing the photoresponsive cyanobacteria (Synechococcus 7942, Syne). Syne exhibits inherent motility and enhanced permeability and retention effects to penetrate deep into the tumor. Under a 660 nm laser irradiation, Syne keeps a controllable, continuous, and robust O-2 production ability through photosynthesis to alleviate tumor hypoxia and reduce monocarboxylate transporter 4 (MCT4) expression and exerts a gentle photodynamic effect by generating reactive oxidative species (ROS) in situ. In addition, adequate O-2 supplement and ROS can not only facilitate intracellular doxorubicin (DOX) accumulation but also increase the drug sensitivity of tumor cells by downregulating the expression of chemoresistance-related genes (e.g., heat shock factor-1, mutant P53, and P-glycoprotein). Compared with free DOX treatment, photoresponsive Syne with laser irradiation facilitates the deep penetration and accumulation of DOX in the tumor. Importantly, this Syne-boosted chemotherapy achieves 100% survival in mice and complete tumor ablation with no evident systemic toxicity over a span of 90 days. Overall, this study presents a new insight and strategy to overcome chemotherapeutic resistance and eliminate tumors.