Paclitaxel induces trained immunity via the GPR183-STING axis to enhance host defense against MRSA infection.

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major global health threat with limited prophylactic options. Trained immunity, characterized by nonspecific functional reprogramming of innate immune cells, offers a promising strategy for infection control. Here, we identify paclitaxel (PTX), a microtubule-stabilizing agent widely used in cancer therapy, as a novel inducer of trained immunity in macrophages. Unlike the microtubule-destabilizing agent nocodazole (Noco), PTX enhanced macrophage proinflammatory responses, phagocytosis, and bacterial killing upon secondary stimulation. Mechanistically, PTX-induced training activated the stimulator of interferon genes protein (STING) pathway, evidenced by increased phosphorylation of STING, TBK1, and IRF3. STING deficiency abolished the trained immune responses and antimicrobial functions. PTX also triggered metabolic reprogramming toward aerobic glycolysis via the Akt-mTOR-HIF1α pathway, which was essential for the trained phenotype. Transcriptomic and functional analyses further revealed that the GPR183-STING axis mediated PTX-induced trained immunity. Inhibition of GPR183 impaired STING activation and suppressed functional responses in vitro. In a murine MRSA pneumonia model, PTX-trained mice showed reduced bacterial burden, preserved lung barrier integrity, and enhanced immune activation, all of which were reversed by GPR183 inhibition or STING deficiency. Collectively, our findings uncover a previously unrecognized immunomodulatory function of PTX and highlight the therapeutic potential of targeting the GPR183-STING axis to enhance trained immunity against resistant bacterial infections.