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

Abstract

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 Cu²⁺ uptake. Cu²⁺ 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.