IFNγ is a cytokine and the only member of the type II interferon family. It plays a crucial role in tissue homeostasis, immune and inflammatory responses, and tumor immunosurveillance, possessing both pro- and anti-cancer properties. Signaling from the IFNγ receptor activates the Janus kinase (JAK) signal transducer and activator of transcription 1 (STAT1) pathway, thereby inducing the expression of canonical interferon-stimulated genes with key immune effector functions.

(Data source: Castro F, et al. Front Immunol. 2018)

IFNγ production

Within the tumor microenvironment (TME), many immune cell subsets, including T cells, natural killer (NK) cells, regulatory T cells, helper T1 (TH1) cells, and CD8 ⁺cytotoxic T lymphocytes (CTLs), produce interferon γ (IFNγ). IFNγ produced by different cell types can have unique and varying effects on its intended targets and bystanders within the TME. Furthermore, the manner in which these cells secrete IFNγ, such as synaptic, leaky synaptic, or multidirectional secretion, can influence the outcomes of IFNγ production.

(Data source: Gocher AM, et al. Nat Rev Immunol. 2022)

IFNγ structure:

IFNγ is composed of 146 amino acids. The protein structure of IFNγ mainly contains α-helix, which allows two IFNγ molecules to dimerize in an antiparallel manner through non-covalent bonds. The IFNγ homodimer forms a hexameric complex by binding to two IFNγR1 subunits and two IFNγR2 subunits.

(Data source: Mendoza JL, Escalante NK, Jude KM, et al. Nature. 2019)

IFNγ signaling pathway and regulation:

The interferon IFNγ receptor, IFNGR, consists of IFNGR1 (α subunit) and IFNGR2 (β subunit). Binding of IFNγ to its receptor activates the canonical Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. Activation of the receptor-associated Janus kinase (JAK) leads to phosphorylation of tyrosine residues in the cytoplasmic domain of the IFNγR, thereby generating substrates for recruitment of signal transducer and activator of transcription 1 (STAT1). Tyrosine phosphorylation of STAT1 promotes dimerization, nuclear translocation, DNA binding to the IFNγ activation site (GAS) element, and transcriptional activation by STAT1 dimers. In addition to inducing STAT1 dimers that bind to GAS elements and cooperate with IFNγ-induced interferon regulatory factors (IRFs), IFNγ can also activate non-canonical transcriptional complexes that resemble the interferon-stimulated gene factor 3 (ISGF3) complexes induced by type I interferons, as they contain IRF9 and bind to interferon-stimulated response elements (ISREs).

(Data source: Ivashkiv LB. Nat Rev Immunol. 2018)

IFNγ in the tumor microenvironment

IFNγ has dual roles in the tumor microenvironment: both anti-tumor and pro-tumor effects. IFNγ promotes the recruitment of immune cells to the tumor microenvironment (TME) through transcriptional regulation of CXCL9, CXCL10, and CXCL11, as well as their cognate receptor, CXCR3, expressed on T cells, NK cells, monocytes, DCs, and cancer cells. Activated CTLs exhibit enhanced chemotaxis to the TME, enhancing cytotoxicity and limiting tumor growth. A key anti-tumor function of IFNγ is its ability to induce expression of MHC class I molecules by APCs, thereby presenting tumor antigens to T cells. The immune-stimulating activity of IFNγ on tumor cells is largely attributed to the induction of MHC class I expression on tumor cells and the secretion of CXCL9, CXCL10, and CXCL11 by tumor cells, monocytes, endothelial cells, and fibroblasts, which promote lymphocyte migration and inhibit angiogenesis (anti-tumor effects). IFNγ can also exert pro-tumor effects by inducing expression of immunosuppressive molecules such as PDL1, IDO1, and iNOS on tumor cells. IFNγ also has a dual regulatory effect on tumor blood vessels and lymphatic vessels, which can inhibit lymphangiogenesis but also indirectly promote tumor angiogenesis.

(Data source: Gocher AM, et al. Nat Rev Immunol. 2022)

IFNγ and cancer immunotherapy

Nearly all cancer immunotherapies, such as recombinant cytokines, vaccines, checkpoint inhibitors, chimeric antigen receptor T cell therapy, and TLR agonists, modulate IFNγ. These therapies are designed to induce inflammation to aid tumor clearance; however, IFNγ-driven adaptive immune resistance can lead to treatment resistance or disease progression. Over the past decade, numerous preclinical studies of IFNγ-modulating immunotherapies have aimed to exploit antitumor effects and block the pro-tumor effects of IFNγ in the TME.

CAR T cell therapy: The IFNγ receptor signaling pathway plays a key role in regulating the adhesion between CAR T cells and solid tumor cells, which provides new ideas for further optimizing CAR T cell therapy for the treatment of solid tumors.

(Data source: Hong L, Ye L. Signal Transduct Target Ther. 2022)

Immune checkpoint blockade: IFNγ plays a key role in immune checkpoint blockade with anti-PD-1 or anti-PD-L1 therapies. Studies have found that IFNγ is localized to areas of melanoma tumors where PDL-1 is highly expressed, suggesting that CTLs may trigger autoinhibition through IFNγ -driven PDL-1 expression. This adaptive immune resistance mechanism may explain tumor evasion of immune surveillance. In addition to driving upregulation of PDL-1 expression, IFNγ produced by CTLs is also essential for mediating their therapeutic effects.