IFNG

Overview

IFNG encodes interferon gamma (IFN-γ), a key pro-inflammatory cytokine produced primarily by activated T cells and natural killer (NK) cells. It is a central mediator of type 1 immune responses, promoting macrophage activation, antigen presentation, and cytotoxic immune function. In biomedical research, IFNG is widely used as a marker of Th1- and Tc1-biased immunity and is frequently measured as an indicator of vaccine immunogenicity, anti-tumor immune activation, and inflammatory disease activity.

Although IFNG is not a structural cellular component in the classical sense, it is often studied in cellular and tissue contexts because its expression reflects immune-cell activation states and immune microenvironment remodeling. Its signaling is closely linked to pathways involving STAT1, antigen presentation, checkpoint regulation, and inflammatory cytokine networks, including IL-2, IL-6, IL-17A, TNF-α, and GM-CSF. In recent studies, IFNG has been repeatedly used as a readout for immune stimulation or suppression across infections, cancer, autoimmunity, and vaccine development.

Focus of Latest Publications

Recent publications have examined IFNG in several immune and disease contexts, most often as part of inflammatory signaling or immune-response signatures. In a multi-omics aging study, two-sample Mendelian randomization of circulating inflammatory proteins identified IFNG as one of the most robust pro-aging mediators across six aging phenotypes, alongside IL-12B and IL-2. That work further integrated summary-based MR with eQTL, sQTL, pQTL, and mQTL resources to map downstream effector genes for epigenetic age acceleration, supporting a broader role for inflammation-linked pathways in biological aging.

IFNG was also implicated in transplant immunology and tissue engraftment. In paired pre- and post-transplant profiling of human embryonic stem-cell-derived retinal pigment epithelium (hESC-RPE), investigators found a Th1-skewed, IFN-γ-rich immune milieu in blood, aqueous humor, and retinal tissue. They showed that IFN-γ-JAK1 signaling promoted an immunogenic state in hESC-RPE, including increased HLA expression and antigen-presentation features, and that brief ex vivo conditioning with ruxolitinib attenuated this response while preserving epithelial properties. In humanized retinal degeneration models, conditioned grafts had reduced T and NK-cell infiltration, improved survival, and better visual function.

Several cancer-focused studies used IFNG as part of immune signatures or immune-phenotype analyses. In melanoma, IFNG was included in an 8-gene VIP-related prognostic signature with CD28, CD80, CD86, CTLA4, FAS, IL10, and IL12A; the signature was associated with overall survival, immune-cell infiltration, and immune checkpoint expression, and was evaluated alongside in silico drug-sensitivity estimates. In colorectal cancer, IFNG expression was analyzed together with CD274/PD-L1 in relation to immune-cell fractions during multi-omics immunophenotyping, helping define immune subtypes and associated prognostic genes. These studies positioned IFNG as a marker of immune activity within the tumor microenvironment rather than as a direct therapeutic target.

IFNG-driven macrophage activation was also central in granulomatous skin disease. Reanalysis of single-cell RNA-seq data from granuloma annulare and cutaneous sarcoidosis, combined with in vitro experiments, showed that IFN-γ activated macrophages through oxidative phosphorylation and an IFN-γ-induced response network sensitive to electron transport chain inhibition. GBP1 was identified as a central regulator of IFN-γ-mediated macrophage activation, and inhibition of IFN-γ signaling, ETC complexes, or GBP1 reduced granuloma formation in a human in vitro model. metformin, as an ETC complex I inhibitor, suppressed IFN-γ activation and granuloma formation.

In cellular immunotherapy, IFNG was measured as a functional readout of CAR-T activity. In HER2-CAR-T cells engineered to secrete IL-12, IFN-γ production correlated with target-antigen density, and IL-12 secretion enhanced tumor-cell killing in gastric cancer models. Together, these recent studies link IFNG to inflammatory aging, graft immunogenicity, tumor immune profiling, granulomatous inflammation, and engineered T-cell function.

Key Publications

NEWJun Genetic and epigenetic underpinnings of biological aging: a multi-omics study integrating Mendelian randomization, spatial transcriptomics, and drug target discovery. (Clinical epigenetics, 2026, PMID 42343471): "Two-sample Mendelian randomization (MR) of 91 circulating inflammatory proteins against six aging phenotypes identified IL-12B, IFNG, and IL-2 as the most robust pro-aging mediators with consistent effects across independent outcomes."
NEWJun Paired pre- and post-transplant human immunoprofiling identifies an IFN-γ-JAK1 axis limiting stem-cell-derived RPE engraftment. (Cell stem cell, 2026, PMID 42309064): "We identify a Th1-skewed, IFN-γ-rich immune milieu across the circulation and eye and show that IFN-γ-JAK1 signaling promotes an immunogenic state in hESC-RPE, marked by increased HLA expression and antigen presentation features."
May Vasoactive intestinal peptide associated 8-gene signature with prognostic and immune associations in melanoma. (Medicine, 2026, PMID 42216340): "In melanoma, we identified an 8-gene signature (CD28, CD80, CD86, CTLA4, FAS, IFNG, IL10, and IL12A) associated with survival."
May A STAT1/ETC/GBP1 axis represents a potential therapeutic target for noncommunicable granulomatous skin disease. (Science advances, 2026, PMID 42213834): "in which the aberrant activation of macrophages by IFN-γ constitutes a central driver."
Apr Integrative multi-omics analysis identified FUT9 and MS4A3 as novel immune-phenotype and prognosis biomarkers for colorectal cancer and analyze the role of FUT9 in oncoimmunology. (Scientific reports, 2026, PMID 41872462): "We calculated Spearman correlation of CD274 (programmed cell death ligand-1, PD-L1) and IFNG (interferon gamma, IFN-γ) expressions with immune cell fraction, and screened different immune cell types with CD274 and IFNG by Lasso regression analysis."
May Evaluation of cross-reactivity of monoclonal antibodies against cytokines and cellular molecules of bovine and human origin to identify immunological markers in buffaloes (Bubalus bubalis). (Veterinary immunology and immunopathology, 2026, PMID 41864098): "sixteen commercial mAbs anti-cell markers (CD4, CD8, CD14, CD21, CD25, CD28, CD45RB, CD45RO, WC1, and CD80) and anti-cytokines or other effector molecules of the immune system (TNF-α, IFN-γ, IL-4, IL-17A, granzyme B and perforin) that recognize molecules from bovine and human species were evaluated in whole blood samples from buffaloes and cattle."
Apr Antigen-induced IL-12 potentiates piggyBac-engineered HER2-CAR-T cells against gastric cancer. (International immunopharmacology, 2026, PMID 41785602): "Functionally, HER2-CAR-T cytotoxicity and IFN-γ correlated with target-antigen density, whereas IL-12 secretion uniformly enhanced tumor-cell killing across both high- and low-antigen tumors."