Interferon (IFN)-mediated antiviral responses are central to host defense against viral infection. First discovered in the 1950s and named for their ability to interfere with viral replication, each type of IFN—type I, II, and III—signals through distinct heterodimeric receptors, IFNRs, and induces gene expression via the kinase-signal transducer and activator of transcription (JAK-STAT) pathway. IFN signaling and viral evasion mechanisms form an extremely complex network that varies across species.

(Data source: Emily VM, et al. Nat Microbiol. 2019)

Type I interferon family

Seventeen type I interferon subtypes have been identified in humans, including 13 IFN-α subtypes, as well as IFN-β, IFN-ω, IFN-ε, and IFN-κ. The 13 human IFN-α subtypes (IFN-α1, IFN-α2, IFN-α4, IFN-α5, IFN-α6, IFN-α7, IFN-α8, IFN-α10, IFN-α13, IFN-α14, IFN-α16, IFN-α17, and IFN-α21) share a high degree of sequence homology (76–96% amino acid sequence sharing [6]), which determines their identical secondary and tertiary folds. This sequence homology is particularly high in their receptor-binding regions, including a conserved hydrophilic region for the IFNAR1-binding region ( blue, residues 74–145) and two conserved hydrophilic regions for the IFNAR2-binding region (green, residues 24–63 and 150–189).

(Data source: Thomas RJM, et al. Eur J Immunol. 2023)

IFN signaling regulation

IFN signaling is divided into two pathways: canonical and non-canonical.

IFN first binds to IFNAR2, and the IFN/IFNAR2 binary complex then recruits IFNAR1 to form a functional ternary signaling complex (IFN/IFNAR1/IFNAR2). Subsequently, Jak1 and Tyk2 kinases pre-bind to IFNAR2 and IFNAR1, respectively. After these kinases and tyrosine residues (red dots) on each receptor phosphorylate each other, members of the STAT (signal transducer and activator of transcription) family bind.

Classical signaling consists of a trimer of pSTAT1, pSTAT2, and IRF9, called ISGF3 (interferon-stimulated gene factor 3). ISGF3 translocates to the nucleus and binds to ISRE (interferon-stimulated response element) to stimulate the transcription of potent ISGs.

One of the non-canonical signaling pathways involves the formation of phosphorylated STAT1 homodimers that bind to the GAS (gamma activation site) promoter element.

(Data source: Megen CW, et al. Front Immunol. 2021)

The most studied members of the type I interferon family are the various IFNα subtypes (IFNα1) and IFNβ. These targets play a role in host resistance to viral infection and in activating key components of the innate and adaptive immune systems, including antigen presentation and the production of cytokines involved in the activation of T cells, B cells, and natural killer cells.

(Data source: Alehashemi, et al. Arthritis Rheumatol. 2025)

Type I IFN -targeted therapy

Targeting the type I IFN /IFNR signaling axis mainly includes antibodies that directly bind to IFNα or IFNβ (sifalimumab, dazukibart), antibodies that block type I interferon receptors (anifrolumab), and small molecule drugs targeting the intracellular Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, also known as JAK inhibitors (tofacitinib, ruxolitinib, baricitinib).

(Data source: Elisabetta B, et al. Biomedicines. 2023)

Currently, Dazukibart and other macromolecular drugs are undergoing clinical trials, while the development of others has been stopped.