Abstract

In solid tumors, the efficacy of adoptive T cell therapy (ACT) is limited by a metabolically constrained tumor environment that undermines T cell persistence, fitness, and infiltration. Here, we engineered a hypoxia-activated bacterial hybrid system (MM@TMV) to address these barriers. This hybrid system integrates metabolically engineered bacteria and tumor membrane vesicles (TMVs) to achieve tumor-restricted metabolic reprogramming and immune reinforcement within hypoxic tumors. Within hypoxic tumors, D-mannose is produced in situ to support stem-like phenotypes and limit exhaustion, while TMVs facilitate both direct and APC-mediated activation of CAR-T and TCR-T cells, concurrently restraining tumor cell growth. In orthotopic, refractory, and metastatic tumor models, MM@TMV further improved T cell persistence, enhanced intratumoral infiltration, and achieved sustained tumor suppression. In a humanized patient-derived xenograft model of Claudin18.2-positive gastric tumors, MM@TMV similarly potentiated clinically relevant ACT. Biosafety tests confirmed systemic safety. Collectively, our findings establish engineered bacteria as programmable immune metabolic modulators that enable effective and safe ACT in solid tumors.