Bacterial metabolic-immune reprogramming in cancer: from living vectors to engineered biofactories.

Tumor immunotherapy has transformed modern oncology, yet its clinical efficacy against solid tumors remains severely restricted by complex physiological and immunosuppressive barriers. Distinct from passive delivery systems, live bacteria can actively navigate into hypoxic tumor cores and intrinsically modulate local immune networks, making them promising intelligent therapeutic vehicles. In this review, we comprehensively trace their evolution from living vectors to engineered biofactories. We discuss how colonizing bacteria reprogram the tumor microenvironment (TME) via metabolic interventions-lactate depletion, hypoxia relief, arginine/tryptophan modulation, and adenosine degradation-to reverse immunosuppression. Furthermore, we highlight how bacteria enhance therapeutic efficacy by facilitating antigen presentation, sharing bacterial antigens, and sensitizing tumors to immune checkpoint blockade. Moving to programmable systems, engineered bacteria can act as biofactories that enable spatiotemporally controlled release of oncolytic toxins, cytokines, and checkpoint nanobodies via synthetic circuits and optogenetic modules. Additionally, we briefly introduce bacterial derivatives and highlight their unique advantages in expanding the immunotherapeutic landscape. Finally, key clinical translational bottlenecks for bacterial platforms are analyzed. Through continued interdisciplinary innovation, intelligent engineered bacteria with multifaceted sensing capabilities may ultimately lead to long-term patient remission.