| Summary: | <jats:title>Abstract</jats:title>
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<jats:p>Combination immunotherapy treatments that recruit both innate and adaptive immunity have the potential to increase cancer response rates by engaging a more complete repertoire of effector mechanisms. Here, we combined intratumoral STimulator of INterferon Genes (STING) agonist therapy with systemically injected extended half-life IL2 and anti–PD-1 checkpoint blockade (hereafter CIP therapy) to drive innate and adaptive antitumor immunity in models of triple-negative breast cancer. Unlike treatment with the individual components, this trivalent immunotherapy halted primary tumor progression and led to long-term remission for a majority of animals in two spontaneously metastasizing orthotopic breast tumor models, though only as a neoadjuvant therapy but not adjuvant therapy. CIP therapy induced antitumor T-cell responses, but protection from metastatic relapse depended on natural killer (NK) cells. The combination of STING agonists with IL2/anti–PD-1 synergized to stimulate sustained granzyme and cytokine expression by lung-infiltrating NK cells. Type I IFNs generated as a result of STING agonism, combined with IL2, acted in a positive-feedback loop by enhancing the expression of IFNAR-1 and CD25 on lung NK cells. These results suggest that NK cells can be therapeutically targeted to effectively eliminate tumor metastases.</jats:p>
<jats:p>See related Spotlight by Demaria, p. 3 .</jats:p>
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