Engineered Probiotics-Based Biohybrid-Driven Tumor Metabolic Remodeling To Boost Tumor Photoimmunotherapy.

Bioengineered probiotics enable new opportunities to address abnormal cancer metabolism and suppressive immune-environment interactions for improved therapeutic susceptibility. Here, Nissle 1917 (EcN) was constructed to convert ammonia into l-arginine continuously and was further modified with polydopamine (PDA) to form living biotherapeutic argEcN@P for enhanced colorectal cancer eradication. Benefiting from the movement of EcN, argEcN@P could colonize and penetrate deep in tumors through hypoxia targeting and increase the intratumoral l-arginine concentrations. Upon near-infrared light (NIR) irradiation, heating induced by PDA could ablate tumor cells efficiently and release tumor antigens, which induce immunogenic cell death (ICD). More interestingly, argEcN@P remarkably promotes differentiation into M1-like macrophages in tumor tissues, inhibiting primary, distant tumor growth by inducing potent adaptive antitumor immunity. More importantly, argEcN@P treatment efficiently prevented postoperative tumor recurrence by inducing long-term immune memory. Taken together, this platform based on bioengineered probiotics provides a promising strategy for tumor metabolic reprogramming sensitized photothermal immunotherapy in deep tumors.