Eliminating intratumoral bacteria with cGAS-STING-activating nanodrug-bacteria biohybrids potentiates cancer immunotherapy.

Breast cancer remains a leading cause of cancer-related mortality in women, with intratumoral bacteria playing a significant role in immunosuppression. However, targeted therapeutic strategies to address this microbial influence remain underexplored. In this study, we developed a novel nanodrug bacteria biohybrid system, LGG-PDA@Cu-CPT, which integrated Lactobacillus rhamnosus GG (LGG) probiotics, polydopamine (PDA), and copper-irinotecan (Cu-CPT) composites to potentiate cancer immunotherapy by simultaneously eliminating immunosuppressive intratumoral bacteria and activating the cGAS-STING pathway, thereby suppressing tumor progression. Photothermal therapy (PTT) mediated by PDA enhanced intratumoral bacterial eradication by disrupting bacterial membranes and promoting intracellular Cu uptake. Cu ions further induced reactive oxygen species (ROS) generation through Fenton-like reactions, effectively killing intratumoral Fusobacterium nucleatum (Fn) bacteria and thereby relieving the bacterium-induced immunosuppressive tumor microenvironment. Concurrently, the acidic tumor microenvironment and PTT-induced heating facilitated the release of CPT, which, together with LGG, activated the cGAS-STING pathway. This activation triggered robust type I interferon production, dendritic cell (DC) maturation, and cytotoxic T lymphocyte (CTL) infiltration, leading to effective immune-mediated tumor cell clearance. Additionally, Fn bacterial remnants acted as immunostimulatory agents, further amplifying immune responses. This synergistic strategy of bacterial elimination and cGAS-STING activation significantly enhanced antitumor immune responses and inhibited tumor progression, providing a promising therapeutic approach for breast cancer treatment.