Revealing an unconventional JAK1/2-STAT3 branch in macrophage IFN-γ signaling

Interferon γ (IFN-γ) is a key cytokine in immune activation, especially anti-viral responses, and a driver of macrophage activation. It classically signals via JAK1/2-mediated STAT1 homodimers. Here, we identify an alternative, non-canonical signaling component in which IFN-γ simultaneously also activates STAT3. Our results show that IFN-γ activates STAT3 rapidly and directly through JAK1 and JAK2. We provide evidence that STAT3 can form heterodimers with STAT1 in this context and demonstrate that STAT3 is co-recruited to a subset of IFN-γ-induced, STAT1-bound regulatory elements. While IFN-γ directly activates STAT3, our results reveal that its contribution to IFN-γ-induced gene expression is limited. Instead, our data indicate that STAT1-STAT3 heterodimers exert a more prominent function in mixed cytokine environments. These findings uncover STAT3 as an unconventional player in macrophage IFN-γ signaling, underscoring the complex and context-dependent nature of cytokine signaling networks.