Cluster of Differentiation 36-Engineered Photosynthetic Cyanobacteria Enable Immunometabolic Reprogramming in...

Triple-negative breast cancer (TNBC) exhibits profound resistance to immunotherapy, largely due to a tumor microenvironment constrained by dysregulated lipid metabolism and persistent hypoxia. Excessive fatty acid uptake mediated by the scavenger receptor CD36 (Cluster of differentiation 36) imposes metabolic stress on immune cells while simultaneously fueling tumor growth, whereas hypoxia independently enforces immune exhaustion and macrophage immunosuppression. Despite extensive efforts, targeting either pathway alone has yielded limited therapeutic benefit, underscoring the need for coordinated immunometabolic intervention. Here, we report a living biohybrid strategy that simultaneously regulates lipid metabolism and oxygen availability to reprogram the TNBC microenvironment. By engineering photosynthetic Synechococcus cyanobacteria with surface-displayed anti-CD36 antibodies, we construct a dual-functional system (Syne@aCD36) capable of blocking CD36-mediated fatty acid uptake while generating oxygen in situ under light stimulation. This coordinated regulation alleviates lipid-induced metabolic stress and hypoxia-driven immune suppression, thereby restoring CD8⁺ T cell cytotoxicity, reversing exhaustion phenotypes, and promoting pro-inflammatory macrophage polarization. In an aggressive 4T1 TNBC model, Syne@aCD36 induces robust tumor growth inhibition, enhances immune infiltration, and exhibits minimal systemic toxicity. This work establishes a previously unexplored paradigm for immunometabolic therapy by integrating metabolic checkpoint blockade with photosynthetic oxygenation, providing a promising strategy for immunometabolic remodeling in lipid-rich and hypoxic tumor microenvironments. STATEMENT OF SIGNIFICANCE: We focus on the fact that excessive fatty acid uptake and tumor hypoxia cooperatively drive immunosuppression and T cell exhaustion in the tumor microenvironment. Our Syne@aCD36 platform possesses two innovations: 1. A dual-function living therapeutic system. Syne@aCD36 blocks CD36-mediated fatty acid uptake on tumor and immune cells while simultaneously generating oxygen through photosynthesis under light stimulation, thereby alleviating lipid metabolic stress and tumor hypoxia in situ. 2. Synergistic immunometabolic reprogramming. By concurrently regulating lipid metabolism and oxygen availability, Syne@aCD36 restores CD8⁺ T cell cytotoxicity, reduces exhaustion phenotypes, and promotes pro-inflammatory macrophage polarization, leading to enhanced immune infiltration and tumor growth suppression. Our study provides a strategy for tumor immunotherapy through integrated regulation of metabolic checkpoints and the tumor microenvironment.