Therapeutic bacteria-trained NK cells confer long-term protection against cancer metastasis.

Metastasis causes 90% of cancer-related deaths, yet preventive strategies remain limited. Here, we report that a single dose of therapeutic Salmonella, a prominent anti-tumor bacterial therapy, provides long-lasting protection against metastasis in mice by inducing "trained" natural killer (NK) cells. Integrated functional and multi-omics analyses revealed that Salmonella-trained NK (stNK) cells establish an enduring reprogrammed epigenome characterized by enhanced pro-survival signaling and immune effector functions, resulting in more potent IFN-γ release and cytotoxicity upon secondary stimulation. We further showed that this training requires a transient pulse of IL-12 combined with sustained IL-18 signaling. Crucially, stNK cells significantly outperform conventional immune checkpoint therapies, including PD-1 and TIGIT blockade, in preventing metastasis, underscoring the unique immunological mechanisms in combating metastasis. These findings highlight the potential of bacterial cancer vaccines or trained NK cells as effective strategies for metastasis prevention.