Engineered commensal Bacteroides thetaiotaomicron enables targeted drug delivery to colorectal tumors.

Microbial therapy has emerged as a promising strategy for cancer treatment, driven by advances in synthetic biology that enable precise engineering of probiotic functions. Engineered bacteria offer several therapeutic advantages, including localized drug delivery, direct tumor killing, and immune modulation. Bacteria-based therapies offer promise for colorectal cancer treatment, yet safety issues of chassis cells and poor targeting remain key challenges. Here, we engineered a novel bacterial system based on the gut symbiont Bacteroides thetaiotaomicron, a naturally abundant and safe resident of the human intestine. By systematically screening BT-derived surface anchors, we established an efficient display system capable of presenting the tumor-targeting protein HlpA on the bacterial surface. Engineered BT demonstrated specific targeting of colorectal tumors in both in vitro cell models and in vivo animal models. Building on this platform, we integrated a therapeutic module encoding hemolysin E, which conferred dual antitumor effects in an AOM/DSS-induced colitis-associated cancer mouse model by alleviating intestinal inflammation and inhibiting tumor growth. Our findings highlight BT as a promising vector for engineered bacterial therapies, providing a new gut symbiont-based targeted cancer treatment strategy.