Temporal dynamics of type I interferon signaling in checkpoint inhibitor response and resistance.

While the long-term efficacy of checkpoint inhibition is established, the lack of response in IFN-rich tumors presents a critical challenge. These findings suggest that immune sensitivity depends on variables beyond cytokine levels and should be assessed in a temporal context. We propose the "IFN clock," in which efficacy is determined by the kinetics of interferon signaling rather than its level. The IFN clock is structured into three phases: a fast-on activation phase, a fast-off recovery phase, and a persistent-on resistant phase. In this model, short-lived interferon signaling supports antitumor immunity, whereas prolonged signaling induces therapeutic resistance. In early signaling, Type I interferon drives immune cell coordination through myeloid priming and chemokine-guided T cell recruitment. Effective outcomes require attenuation of signaling; loss of feedback control promotes chronic interferon exposure. Persistent activation results in stable epigenetic remodeling that enforces immune evasion and progressive T cell dysfunction. We introduce the dISG ratio to operationalize this framework. It provides a transcriptomic metric that separates acute from chronic interferon states, enabling patient stratification. Emerging preclinical evidence suggests that modulating interferon kinetics may restore checkpoint blockade sensitivity, though clinical validation remains limited. The IFN clock reframes interferon biology as dynamic and time-dependent. It offers a framework for biomarker refinement and therapeutic design.