STAT3 operates as an inflammation-dependent transcriptional switch in antiviral NK cells.

The immune system integrates signals to regulate immune responses, forming complex context-dependent networks where identical cues produce distinct outcomes. Signal transducer and activator of transcription (STAT) transcription factors convert cytokine receptor engagement into transcriptional responses, serving as central regulatory hubs. How concurrent STAT activation across different environments shapes immune cell function remains unclear. Here, we show that STAT3 plays a context-dependent role in antiviral natural killer (NK) cells, either promoting or impairing adaptive responses depending on the inflammatory milieu during mouse cytomegalovirus (MCMV) infection. STAT3 is recruited to distinct genomic loci depending on IL-15 or type I interferon availability, thus driving alternative transcriptional programs. Mechanistically, STAT3 differentially regulates downstream transcription factors MYB and B lymphocyte-induced maturation protein-1 (BLIMP-1) to shape NK cell differentiation during homeostasis and infection. STAT3 relocation is governed by epigenetic mechanisms and preferred relocation toward distinct STAT motifs. Thus, STAT3 functions as a cytokine-sensing transcriptional switch integrating IL-15 and type I interferon signals to control lymphocyte adaptation during viral infection.