Chemo-immunotherapeutic potential of Lactobacillus rhamnosus GG and its bioengineering for cancer therapy

Bacteriotherapy holds great promise for cancer treatment, yet few bacterial agents have progressed to clinical application. Inspired by the acidic growth conditions of Lactobacillus rhamnosus GG (LGG), which resemble the tumor microenvironment, we systematically investigated its intrinsic anti-tumor potential. LGG demonstrated acid-environment tropism, strong adhesion to tumor cells, and active penetration into deep tumor tissues. Both LGG and its secretions exhibited potent cytotoxicity against various tumor cell lines, associated with mitochondrial dysfunction and apoptosis, likely due to acidification of the surrounding environment. Furthermore, LGG competitively inhibited tumor-promoting bacteria and activated immune responses by promoting M1-type macrophage polarization and dendritic cell maturation. To enhance its therapeutic efficacy, we further developed a biohybrid system by conjugating paclitaxel-loaded poly (lactic-co-glycolic acid) nanoparticles to LGG (PTX-NPs-LGG), enabling both targeted chemotherapy and bacteriotherapy. Additionally, a thermo-sensitive hydrogel was employed for peritumoral delivery, ensuring sustained release and localized activity. In the 4T1 breast tumor lung metastasis model and the B16F10 tumor postoperative recurrence model, PTX-NPs-LGG@gel exhibited superior anti-tumor efficacy with favorable safety profiles. These findings highlight the potential of LGG-based biohybrids as a safe and effective platform for chemo-immunotherapy in cancer treatment.