Engineered probiotics potentiate radiotherapy-induced antitumor immunity in rectal cancer via spermine-mediated immunometabolic reprogramming

Low rectal cancer remains a significant clinical challenge due to its intricate anatomy and limitations of conventional treatments. In this study, we engineered the probiotic Escherichia coli Nissle 1917 (EcN) to colonize the colorectal region and continuously release spermine, establishing an engineered probiotic platform termed EcN-SPL@L100. This natural polyamine delivery system stabilizes cGAS–DNA interactions and amplifies cGAS–STING signaling, thereby enhancing local innate antitumor immunity. To further improve therapeutic efficacy, EcN-SPL@L100 was combined with the radiolabeled peptide 177 Lu-c(RGDfK). Ionizing radiation from 177 Lu induced cytosolic accumulation of tumor DNA, which synergized with EcN-SPL@L100-mediated cGAS–STING activation to promote immunogenic cell death and proinflammatory cytokine secretion. Meanwhile, radiation upregulated spermine oxidase (SMOX), accelerating the conversion of spermine delivered by EcN into spermidine. This metabolic shift fostered dendritic cell maturation, CD8 + T cell infiltration and adaptive immune activation. In a murine model of low rectal cancer, this combination strategy significantly inhibited tumor growth, prolonged survival and preserved intestinal barrier integrity without systemic toxicity. Our findings demonstrate that integrating a spermine-releasing probiotic platform with targeted radionuclide therapy effectively remodels tumor metabolism and immunity, representing a safe and promising approach for low rectal cancer. The design of an engineered probiotic liposome delivery system for the sustained release of spermine combined with 177Lu-c(RGDfK) achieves an organic integration of local tumor ablation with synergistic innate and adaptive immunity activation to provide a safe and effective therapeutic strategy for low rectal cancer.