The effects of IFNγ on tissue physiology through structural cells

Interferon-γ (IFNγ) is classically defined by its potent ability to enhance the antimicrobial and tumour-killing activities of innate and adaptive immune cells, establishing it as an archetypal pro-inflammatory type 1 cytokine. However, as the most conserved of the interferons throughout evolution, it is possible that IFNγ may have a more fundamental physiological role beyond these immune functions. A rapidly growing body of literature now indicates that IFNγ acts extensively on non-haematopoietic, structural cells to regulate organ function, tissue homeostasis and context-dependent immune adaptation. These findings position IFNγ as a primary coordinator of diverse defence strategies, including host resistance, disease tolerance and trained immunity. In this Perspective, we examine how IFNγ signalling in non-haematopoietic cells complements or alters its canonical immune functions and argue that defining the context-specific and cell-specific actions of IFNγ is essential to inform therapeutic approaches targeting IFNγ that enhance immunity while preserving tissue function.