Tumorigenesis is a complex pathological process that is regulated by multiple molecular mechanisms, such as genome mutation and instability, epigenetic alterations, and abnormal activation of cellular signaling pathways. To eliminate tumor cells and avoid immunopathological consequences, both the innate and adaptive arms of the immune system work to provoke regulatory mechanisms and deliver an efficient response.
IFNγ, a type II IFN secreted by specialized immune cells, is thought to be critical for the antitumor immune response in many types of cancers. IFNγ was first identified due to its effect on virus infection. Currently, accumulated evidence has found that IFNγ plays pleiotropic roles in tumor regression and progression as well. IFNγ is produced by restricted immune cells, such as activated T cells and natural killer (NK) cells, and exerts its antitumor effects through the activation of the IFNγ-mediated signaling pathway and the expression of IFNγ-stimulated genes (ISGs). Activation of the IFNγ signaling pathway may provide a novel option for tumor immunotherapy. In addition to adverse effects in patients with cancer, patients resistant to IFNγ-dependent immunotherapies commonly have molecular aberrations in the IFNγ signaling pathway or express resistance molecules driven by IFNγ. Therefore, it is critical to understand the mechanisms by which tumor cells develop primary and acquired resistance to IFNγ-induced therapies. In this review, we focus on IFNγ signaling, regulatory mechanisms, antitumor functions, and tumor immune escape mechanisms in response to IFNγ treatment.
Data sources and study selection
This review developed the search strategy involved the searches of PubMed, Scopus databases, and manual selection of relevant articles. We focused on literature containing key words for IFNγ and cancer from 1957 to 2022, particularly in the last decade. Various terms in conjunction with IFNγ were used, including cancer, pancreatic cancer, signaling pathway, tumor immunosurveillance, immune evasion, and immune therapy. Original articles, review articles, and meta-analyses relevant to the review theme were taken into consideration.
IFNγ production and signaling
Cellular IFNγ production in the tumor microenvironment
In the TME, IFNγ is primarily produced by immune cells, including innate-like lymphocytes, such as NK cells, and adaptive immune cells, such as CD4+ T helper type 1 (Th1) cells and CD8+ cytotoxic T cells. IFNγ expression is tightly regulated at the epigenetic, transcriptional, post-transcriptional, and post-translational levels. These mechanisms prevent IFNγ expression by non-immune cells, naive T cells, and even some activated immune cells.
NK cells are primarily involved in the production of IFNγ in innate immunity. Mature NK cells contain epigenetic open marks on the Ifng promoter, leading to their constitutive expression of Ifng transcripts, and allowing for rapid production and secretion of IFNγ in response to infection or cancer. In NK cells, IFNγ can be induced by cytokines, such as IL-2, IL-12, IL-15, and IL-18,[12,13] as well as through NK activating receptor-mediated pathways. Regarding the receptor-mediated mechanism, immunoreceptor tyrosine-based activating motifs (ITAMs) phosphorylate protein tyrosine kinases (PTKs) of the Src family, leading to the activation of mitogen-activated protein kinases (MAPKs) to release IFNγ.
CD8+ and CD4+ T cells are major sources of IFNγ in the adaptive immune cells. Among CD4+ effector lineages, only Th1 cells produce a substantial amount of IFNγ to sustain an effective cellular immune response. Furthermore, most studies have suggested that CD8+ cytotoxic T lymphocytes (CTLs) are one of the most essential producers of IFNγ in response to inflammatory or immune stimulation.[15,16] CD4+ Th1 and CD8+ T cells begin to rapidly produce and secrete IFNγ after activation and differentiation. IFNγ secretion from both CD4+ and CD8+ T cells is mediated by both receptor- and cytokine-dependent mechanisms, and the cellular pathways are similar to the pathways already described in NK cells. Following the interaction between the T-cell receptor (TCR) and its cognate antigen, a variety of Src family tyrosine kinases are activated, eventually resulting in the activation of MAPKs, which then transcriptionally upregulate IFNγ via further activation of the transcription factors Jun and Fos. Similar to NK cells, IL-12 and IL-18 are capable of eliciting IFNγ secretion in previously differentiated CD4+ Th1 and cytotoxic CD8+ T cells. In addition, the way in which IFNγ is secreted can also affect the outcome of IFNγ production. CTLs secrete IFNγ in a leaky synaptic manner, which ensures that the target cells receive concentrated IFNγ signals to mediate targeted cell killing. In contrast, NK cells release IFNγ in a multidirectional manner. Herein, different immune cell subsets may regulate IFN-γ production in different ways at different levels.
Regulation of IFNγ
As a critical cytokine in controlling both the innate and adaptive immune systems, either underexpression or overexpression of IFNγ exerts deleterious effects on the immune system. A series of regulatory elements are used to achieve tight control of IFNγ, mainly at the transcriptional, epigenetic, and post-transcriptional levels.
The production of IFNγ is correlated with the activation of special immune cells, and which are regulated by amounts of transcription factors. Of note, T-cell–specific T-box transcription factor (T-bet) is considered as a key activator of IFNγ production by promoting Th1 cell differentiation. In contrast to CD4+ T cells, the expression of IFNγ by CD8+ T cells is independent of T-bet and requires the transcription factor eomesodermin (EOMES). Furthermore, the presence of many transcriptional repressors is necessary to avoid the overexpression of IFNγ, such as downstream regulatory element antagonist modulator (DREAM), prospero-related homeobox (Prox1), and GATA Binding Protein 3 (GATA3). DREAM inhibits IFNγ transcription levels via directly binding to the promoter region of Ifng gene. Prox1 downregulates IFNγ expression by repressing the activity of the Ifng promoter, which is largely dependent on its interaction with peroxisome proliferator-activated receptor gamma (PPARγ). Moreover, GATA3 inhibits the expression of IFNγ by blocking the functions of RUNX family transcription factor 3 (Runx3) and T-bet.
In practice, the regulation of IFNγ transcription not only can be mediated by the selective action of transcription factors but also by the modification of the chromatin template at a gene locus. Epigenetic histone marks and DNA methylation status have been shown to contribute to its transcriptional activation or silencing. As described above, the production of IFNγ is associated with the differentiation of CD4+ T cells and CD8+ T cells. In fact, the Ifng locus undergoes complicated and dynamic changes in histone modification in differentiating lymphocytes. The Th1 differentiation program drives H4 acetylation modification across the Ifng locus and promotes the transcription of IFNγ. Notably, the upregulation of H4 acetylation levels is dependent upon the transcription factor T-bet. Furthermore, the Th1 differentiation program also stimulates the modification of H3K4 methylation to promote transcription. By contrast, H3K9 methylation, a transcriptional repressor marker, maintains high levels at Ifng gene loci in developing Th0 and Th1 cells. Similar evidence has been shown that repressive H3K27me3 and H3K27me2 levels are reduced but H3K4me3 is increased at the Ifng locus in memory CD8+ T cells. In principle, the accumulation of excess IFNγ has deleterious effects through disrupting the balance of pro-inflammatory and anti-inflammatory processes. The dynamic nature of histone modifications is beneficial for achieving proper control of IFNγ production.
DNA methylation is a major epigenetic mechanism that modifies DNA by methylating cytosine bases at the carbon-5′ position in CpG dinucleotide residues, thereby often regulating gene expression and integrity. In general, DNA methylation is largely lost during Th1 differentiation. Several DNA methyltransferases (DNMTs) that can maintain DNA methylation at the Ifng locus and keep CD4+ T cells in an undifferentiated state. The utilization of 5-azacytidine (5-AZA), which causes DNA demethylation, also leads to increased levels of IFNγ in CD8+ T cells.
Post-transcriptional regulation of IFNγ is mostly targeted at the stabilization of IFNγ mRNA. On the one hand, AU-rich elements (AREs) within the Ifng 3′ untranslated region (3′UTR) restrict its mRNA stability and limit its protein synthesis. On the other hand, Ifng mRNA activates RNA-activated protein kinase (PKR) through a 5′-proximal pseudoknot, resulting in eIF2α phosphorylation and attenuation of its own translation. In addition, Salerno et al. found that protein kinase C (PKC) not only promoted the transcription of IFNγ but also mediated its mRNA decay to regulate IFNγ at the post-transcriptional level.
In conclusion, IFNγ production is influenced by a variety of distinct regulatory mechanisms which can lead to a balance of IFNγ expression and maintain an efficient cellular immune response. However, a large number of studies have found that the biological function of IFNγ was largely dependent on the activation of its downstream signaling pathway. Thus, much effort has been devoted to the mechanistic study of the IFNγ signaling pathway.
IFNγ signaling pathway
As previously reported, IFNγ exerts its biological effects by activating its well-controlled molecular signaling networks, mainly through the JAK-STAT pathway. Binding of IFNγ to its cell surface receptor results in oligomerization of IFNγR1 and IFNγR2 and leads to the activation of both Janus kinases JAK1 and JAK2 by autophosphorylation and transphosphorylation, which in turn recruits and phosphorylates signal transducer and activator of transcription 1 (STAT1).[34,35] Phosphorylated STAT1 dissociates from its receptor binding site, and translocates to the nucleus as homodimers, where it binds to a specific DNA motif called the “gamma-activated site” (GAS) to activate the transcription of ISGs. Recent work has identified that most ISGs have both positive and negative effects on the inflammatory process and immunity. In addition, many ISGs belong to the member of the IFN regulatory transcription factor family, leading to the transcription of secondary response genes. For example, as one of the major ISGs, induced interferon regulatory factor 1 (IRF1) further upregulates the expression of a large number of genes related to multiple biological processes in cancer cells, such as cell cycle arrest, apoptosis, and tumor suppression.[38,39] Collectively, these studies support a critical role of JAK-STAT1-ISGs and its feedback loop in mediating immune responses and associated tumor immunosurveillance.
In addition, increasing evidence suggests the activity of the JAK-STAT1-ISGs pathway can be modulated at multiple levels. Polycomb repressive complex 2 (PRC2) catalytic subunit EZH2, a key enzyme of H3K27me3, can inhibit the IFNγ-JAK-STAT1 signaling. Mechanistically, EZH2 directly silences the IFNγ receptor 1 (IFNγR1) in prostate cancer cells, which is dependent on MYC, resulting in the inactivation of IFNγ-JAK-STAT1 signaling and tumor cell insensitivity to IFNγ treatment. As a typical model of histone modification, histone deacetylase (HDAC) inhibitor block IFNγ-mediated STAT1 phosphorylation and lead to the downregulation of target genes.[41,42] In addition, Xu et al reported that the DNA demethylase Tet methylcytosine dioxygenase 2 (TET2) acts as an important regulator in the IFNγ-JAK-STAT signaling pathway. The binding of IFNγ induces STAT1 to recruit TET2 to control chemokine and PD-L1 gene expression, further enhancing the efficacy of antitumor immunotherapy.
Moreover, post-transcriptional modification of key mediators, via phosphorylation, palmitoylation, and SUMOylation, is also crucial for maintaining the homeostasis of the IFNγ signaling pathway. It has been proven that glycogen synthase kinase 3 beta (GSK3β) enhances IFNγR1 protein stability by phosphorylating IFNγR1 and further limits its ubiquitin-proteasome degradation. Activation of fibroblast growth factor receptors (FGFRs) signaling inhibits the IFNγ-stimulated STAT1 phosphorylation and the expression of downstream genes, including B2M, CXCL10, and PD-L1. Therefore, FGFR inhibition with lenvatinib could enhance antitumor immunity and the efficacy of immune checkpoint blockade (ICB). Moreover, a recent study showed that the interaction of optineurin with adaptor-related protein complex 3 subunit delta 1 (AP3D1) blocks AP3D1-mediated palmitoylated-IFNγR1 lysosomal sorting and degradation. In other words, loss of optineurin attenuates the expression of IFNγR1 and MHC-I, thereby impairing antitumor immunity in colorectal cancer. In addition, small ubiquitin-like modifier (SUMO) overexpression promotes STAT1 SUMOylation and leads to the inhibition of IFNγ-induced STAT1 phosphorylation. STAT1 inactivation attenuates the transcription of ISGs and further affects tumor cell sensitivity to IFNγ.
In addition, recent studies have reported that other pathways regulate many facets of IFNγ biological actions by either cooperating with or acting in parallel with the JAK-STAT signaling pathway. Gao et al revealed the existence of crosstalk between the JAK-STAT1 and PI3K-AKT pathways in lung adenocarcinoma cells in response to IFNγ. The mechanistic investigation demonstrated that IFNγ induced both the activation of the JAK-STAT pathway and PI3K-AKT pathways, and in turn, IFNγ-induced STAT1 transcriptional activity was dependent on PI3K-AKT. In addition, a PI3K inhibitor (LY294002) significantly downregulates the expression of ISGs, including CXCL9, CXCL10, and PD-L1. Other studies have also found that c-SRC and CAMKII regulate the transcriptional activity of STAT1 in response to IFNγ.[49,50] In addition, Gough et al reported that IFNγ stimulated JAK1-STAT1-independent activation of the MEK/ERK/c-JUN signaling pathway, which contributed to the induction of several ISGs. Taken together, the IFNγ signaling pathway can be modulated by multiple regulatory mechanisms, which have significant implications in IFNγ-dependent biological effects and tumor immunity. However, further studies are needed to fully explore the multilevel regulation of IFNγ signaling in different contexts.
The effect of IFNγ on tumor cells and the TME
Our understanding of the role of IFNγ in tumor development and progression has evolved over the past few decades. The role of IFNγ in the tumor microenvironment (TME) extends beyond targeting immune cells. It has been proven that IFNγ exerts pleiotropic effects by modulating the function of tumor cells, immune cells, and other stromal cells in the TME.
Effects on tumor cells
A large number of studies have demonstrated that IFNγ triggers cell cycle arrest in several types of cancer. Hobeika et al reported that IFNγ blocks the cell cycle of DU145 cells by promoting p21waf1 expression, which was attributed to increased binding of p21 with both CDK2-Cyclin E complexes and proliferating cell nuclear antigen (PCNA). Vivo et al also found that the proliferation of HM cell lines is restrained by IFNγ stimulation. Many cell cycle regulators, such as CDK1, p27waf1/cip1, and p27Kip1 are reduced in response to IFNγ, which results in cell cycle arrest at both G1/S or G2/M phase. For example, IFNγ causes B16 melanoma cancer cells to arrest in G1 phase via regulation of the Skp2/p27-mediated cell cycle. As described above, IFNγ-induced antiproliferative effects are mainly through regulating the expression of cyclin-dependent kinase.
In addition to the role in cell cycle arrest, recent studies have provided a novel view that the combination of IFNγ with TNFα drives tumor cells into senescence. Braumüller et al reported that IFNγ together with TNFa drove cancer cells into senescence by inducing permanent growth arrest in the GO/G1 phase. Cytokine-induced senescence is dependent on STAT1 and TNFR1 signaling but not cyclin-dependent kinase inhibitor 2A (CDKN2A), which is different from oncogene-induced senescence. Furthermore, Hubackova et al identified that IFNγ/TNFa-evoked oxidative stress, DNA damage, and cellular senescence through transforming growth factor-β (TGFβ)/small mother against decapentaplegic (SMAD) signaling-dependent induction of NADPH oxidase 4 (NOX4) and inhibition of adenine nucleotide translocase 2 (ANT2).
In recent years, many research interests have focused on illustrating the biological process of cell death triggered by IFNγ, including apoptosis, autophagy, ferroptosis, and PANoptosis. IFNγ promotes apoptosis through direct affecting death receptors or components of the apoptotic machinery in many types of cancer cells. IFNγ induces caspase-8 and caspase-1 to promote cell apoptosis in a STAT1/IRF1-dependent manner in various tumor cell lines. In addition, IFNγ triggers unique mitochondria-mediated apoptosis via RNase L. The activation of RNase L by IFNγ promotes the formation of Bax-Bak heterodimers and Bak homodimers in mitochondria, and then leads to cytochrome C release and the Caspase-9–Caspase-3–PARP cascade activation.
In addition, several studies have revealed the important role of autophagy in the regulation of cell survival except for the effect of apoptosis. Wang et al suggested that IFNγ induces mitochondrial ROS production dependent on cytosolic phospholipase A2 (cPLA2). The accumulation of mitochondrial ROS promotes autophagy and autophagy-associated apoptosis in colorectal cancer cells. Furthermore, there is evidence that the activation of IFNγ-induced JAK1/2-STAT1 and AKT-mTOR signaling boosts the induction of UPR and ER stress. This ER stress contributes to the impairment of autophagic flux by reducing LAMP-1 and LAMP-2 expression, and thereby affects the biological consequences of apoptosis. In addition, IFNγ also induces autophagy-mediated cell death via the IRF1 signaling pathway in hepatocellular carcinoma cells. The consequences of IFNγ-triggered autophagy may shed light on novel mechanisms underlying IFNγ-mediated antitumor effects.
Ferroptosis is a new type of programmed cell death that is different from apoptosis, necrosis, and autophagy. It is caused by iron-dependent lipid peroxidation and massive accumulation of reactive oxygen species. Wang et al reported that IFNγ from CD8+ T cells inhibits SLC3A2 and SLC7A11 levels thereby facilitating tumor cell lipid peroxidation and inducing ferroptosis. Yu et al also identified that the activation of IFNγ signaling triggers Erastin-induced ferroptosis via downregulation of SLC7A11 in adrenocortical carcinoma (ACC). In addition, it was reported that IFNγ combined with radiotherapy enhanced ferroptosis by inhibiting the expression of SLC7A11, providing a new concept for antitumor therapy. Moreover, Liao et al discovered crosstalk between the immune system and lipid metabolism in the regulation of ferroptosis. They found that the combination of CTL-derived IFNγ and arachidonic acid (AA) triggered the ferroptosis of tumor cells via ACSL4. Notably, recent research revealed that IFNγ promoted tumor cell PANoptosis through the upregulation of IFN-stimulated genes (ISGs) involving Z-DNA binding protein 1 (ZBP1) and adenosine deaminase RNA-specific (ADAR1), which is an inflammatory programmed cell death regulated by the PANoptosome complex with key features of pyroptosis, apoptosis, and necroptosis.
Overall, these evidence show that IFNγ exerts its cytotoxic effects on the tumor cells through distinct mechanisms. With the increasing application of immunotherapy and traditional chemotherapy, whether IFNγ and other toxic drugs have any synergistic killing effects deserves further investigation.
Effects on immune cells
All nucleated cells constitutively express IFNGR1 and can respond to IFNγ. Therefore, the pleiotropic effects of IFNγ in the TME are complex and the overall impact on tumor growth depends on the balance of antitumor IFNγ signaling and protumor IFNγ signaling. Here we focused on IFNγ responders in the TME, including macrophages, NK cells, antigen-presenting cells (APCs), and T cells.
IFNγ was the first described macrophage-activating factor (MAF) responsible for inducing polarization of these cells toward the tumoricidal M1 phenotype. The cooperation of IFNγ with Toll-like receptor (TLR) agonists promotes optimal induction of the tumoricidal M1 macrophage phenotype as well as the production of nitrogen monoxide (NO) and secretion of pro-inflammatory cytokines (TNF-α, IL-12p40, and IL-12p70). Moreover, a recent study found that the cooperation of IFNγ and CCL-2–redirected tumor-infiltrating monocytes/macrophage, which facilitated the depletion of cancer fibrosis and led to enhanced chemotherapy efficacy in pancreatic ductal adenocarcinoma cancer (PDAC). In fact, IFNγ induces inducible nitric oxide synthase (iNOS) positive M1 macrophages, which can modulate endothelial cell activation and Th1 cell recruitment via the upregulation of vascular cell adhesion protein-1 (VCAM-1) and the Th1 trafficking chemokine RANTES, respectively. Due to the high plasticity of macrophages, the antitumor phenotype and function of M1 macrophages may be altered by the TME during tumor progression. Additionally, IFNγ suppressed tumor-derived CXCL8 to inhibit CXCR2+ macrophage infiltration, therefore blocking the CXCL8/CXCR2 axis would improve the efficacy of PD1 blockade therapy.
NK cells are crucial for the innate immune response to cancer cells. Meissl et al found that STAT1α promoted NK cell maturation which relies on the IFNγ signaling cascade under homeostatic conditions. IFNγ secreted by bystander T cells also promoted NK cells maturation through TNF-related apoptosis-inducing ligand (TRAIL), which can be enhanced by interferon regulatory factor (IRF)-1. In addition, the expression of CXCR3 induced by IFNγ is a key requisite for NK cell tumor infiltration, thus contributing to NK cell–based antitumor immunotherapies.
The APCs, such as dendritic cells (DCs) and macrophages, serve as important bonds between tissue-derived signals and T-cell activation during the adaptive immune response. IFNγ can induce the expression of the major histocompatibility complex (MHC) molecules on APC cells, thereby promoting CD4+ T-cell activation. In addition, induction of DC maturation under IFNγ stimulation enhances CTL function and Th1 differentiation by promoting the expression of costimulatory molecules and cytokines, such as CD40, CD54, CD80, CD86, IL-12, and IL-18.[77,78]
CD4+ T cells
The feedback loop between IFNγ and CD4+ Th1 cells has been well demonstrated. On the one hand, CD4+ Th1 cells are a major source of IFNγ. On the other hand, IFNγ together with IL-12 can induce and maintain the stabilization of the Th1 phenotype through the IFNγ-activated transcription factors STAT1 and T-bet.[80–82] In addition, IFNγ has an inhibitory effect on the differentiation of other T helper cells, such as Th2 and Th17 cells. IFNγ-induced T-bet suppresses Th2 cell differentiation via directly inhibiting the Th2 cell-specific transcription factor GATA3. Furthermore, it has been reported that the Th2 cytokine IL-4, which promotes GATA3 expression, can be inhibited by IFNγ-induced SOCS1. Indeed, IFNγ also impedes Th17-cell subset development by inhibiting the expression of the Th17-cell lineage–specific transcription factor RORγt.
CD8+ T cells
As one of the most essential producers of IFNγ, the activity of CD8+ T cells is also regulated by IFNγ. IFNγ triggers the expression of T-bet, IL-2 receptor, and granzyme B (GzmB), thereby contributing to enhanced CD8+ T cell cytotoxic activity and IFNγ production. Lately, a study demonstrated that IFNγ induced the expression of Survivin and Ifi202, which contributed to CD8+ T cell maturation, survival, and proliferation. Additionally, IFNγ enhances CTL motility through chemokine-dependent mechanisms. Increased chemokines, such as CXCL9, CXCL10 and CXCL11 regulated by IFNγ, promote the recruitment of CTL at the tumor site and further elicit antitumor effects.
Effects on other cells in the TME
Although IFNγ can impede tumor growth by acting directly on cancer cells, it also acts on the tumor stroma to inhibit tumor progression, such as cancer-associated fibroblasts (CAFs), and endothelial cells. Recent studies have also emphasized the key role of angiogenesis in the TME, as tumor cells have high demands for nutrients and oxygen. IFNγ was reported to have antiangiogenic effects. Furthermore, Lu et al reported that IFNγ impaired the function of pro-tumoral fibroblasts, which further inhibited the expression of vascular endothelial growth factor (VEGF) and blocked angiogenesis in the TME. A recent study determined that responsiveness to IFNγ by myeloid cells, T cells or fibroblasts, was insufficient for IFNγ-induced tumor regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumor vasculature, resulting in the arrest of blood flow and subsequent collapse of the tumor. In summary, IFNγ acts on tumor cells, immune cells, and stromal cells either directly or indirectly, to synergistically enhance the antitumor effect of IFNγ.
Escape from IFNγ-dependent immunosurveillance
As described above, IFNγ exerts its antitumor effect by affecting various components in the TME. However, during the cancer development and progression, tumor cells develop strategies to overcome the IFNγ-dependent immunosurveillance, including the induction of immunosuppressive factors, hypo-responsiveness to IFNγ, and nutrient competition.
Induction of immunosuppressive factors
Like most cytokines, IFNγ induces feedback inhibitory mechanisms to restrain the overactivation of immune responses. In tumors, IFNγ induces the expression of inhibitory molecules, such as programmed cell death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), and arginase, which might lead to IFNγ-dependent immune evasion via acting on immune cells in TME. As a membrane-bound immune inhibitory molecule, PD-L1 stimulates apoptotic T cell death and downregulates T cell–mediated immune responses through binding to programmed cell death protein 1 (PD1), which is expressed on activated T cells.[93,94] PD-L1 are wildly expressed in TME, not only on tumor cells, but also on other stromal cells and myeloid cells.[95,96] The discovery has led to the use of antibodies that block PD-1 or its ligands PD-L1 to induce antitumor T cell responses and has revolutionized cancer immunotherapy. Recently, a large number of studies demonstrated that direct contact between tumor cells and T cells is necessary for the induction of PD-L1 and suggested IFNγ secreted from T cells plays an important role in the induction of PD-L. To avoid the T-cell attack, cancer cells employ the IFNγ-JAK-STAT1 pathway to enhance PD-L1 expression and attenuate immunosurveillance. In addition, IFNγ induces the expression of IDO in tumor cells, which is a kynurenine pathway enzyme that catalyzes the first-rate limiting step of the degradation of Trp to kynurenine (Kyn) and modulates immunity toward immunosuppression.[99,100] Mechanistically, the activation of canonical JAK-STAT1 signaling pathway induced by IFNγ promotes the expression of IDO1, which consequently blunts CTL-mediated antitumor response via Treg-dependent immune suppression. Arginase is the manganese enzyme that hydrolyzes L-arginine into ornithine and urea. Arginase expression induced by IFNγ contributes to supporting the functions of tumor-associated macrophages, DCs, and MDSCs in the TME. In addition to being dependent on IFNγ, tumor cells can escape immune surveillance in an IFNγ-independent manner. For example, the activation of the epidermal growth factor receptor (EGFR) signaling pathway induces the upregulation of PD-L1 and leads to a decrease in cytotoxic T cells in non-small cell lung cancer (NSCLC). Another study showed that IL-6 triggers phosphorylation of JAK1, which promotes PD-L1 interaction with STT3 and PD-L1 glycosylation to maintain its stability. In addition to PD-L1, immunoglobulin-like transcript (ILT)4, which is induced by EGFR-AKT/-ERK1/2 signaling, also inhibits the proliferation and cytotoxicity of T cells in NSCLC. Whether other pathway interplays IFNγ-induced PD-L1 expression needs further exploration.
Hypo-responsiveness to IFNγ
Tumor cells tolerate the IFNγ-induced antitumor signaling due to cellular hypo-responsiveness. IFNγ exerts biological effects via the IFNγ-induced signaling, particularly the JAK-STAT signaling pathway. Growing evidence suggests that mutations in JAK1 and JAK2 genes in many cancer types lead to a poor response to IFNγ, thereby suppressing the cytotoxicity of CD8+ T cells.[107,108] Moreover, the aberrant activation of srchomology 2-containing phosphatase (SHP) 2 occurs in many cancer types, which induces the activation of the MARK/ERK-mediated signaling pathway and blocks the IFNγ-mediated antitumor signaling, resulting in poor response of tumor cells to IFNγ treatment.[109–111] Similarly, the aberrant expression of the BRG1-associated factor (PBAF) complex, encoded by ARID2 and PBRM1, also weakens the responsiveness of tumor cells to IFNγ.
Recent studies have shown that tumor cells evade immune surveillance by imposing nutrient deprivation or rewiring the cellular metabolism of T cells to disrupt their antitumor activity. Chang et al reported that tumor cells impaired TIL function to produce effector cytokines (eg, IFNγ) via glucose competition. Glucose deprivation leads to the dysfunction of N-linked protein glycosylation in T cells and results in the inhibition of IFNγ production, which is mediated by the IRE1α-X-Box binding protein 1 (XBP1) axis in ovarian cancer. Enhanced glycolytic activity of cancer cells further limits the ability of effector T cells to produce IFNγ via increased expression of tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage CSF, thereby facilitating the infiltration of MDSCs. Accelerated glycolytic metabolism in cancer cells also causes an increase in lactate, which dampens cytokine secretion by tumor-infiltrating T cells and NK cells, thereby promoting immune escape and tumor growth. Furthermore, upregulation of the methionine transporter SLC43A2 in tumor cells outcompetes CD8+ T cells for methionine metabolism, resulting in decreased expression of STAT5 and IFNγ in CD8+ T cells.
IFNγ-based immune therapy
Activation of IFNγ signaling
Based on the pleiotropic functions of IFNγ on the tumor cells, immune cells and the surrounding microenvironment, activation of the IFNγ signaling pathway has emerged as a promising therapeutic strategy against tumor progression. Currently, to activate IFNg signaling, 2 major strategies have been developed: systematic direct administration of recombinant IFNγ or activation of the cGAS/stimulator of interferon genes (STING) pathway to drive the production of type I IFNs, thereby indirectly promoting IFNγ production. The administration of IFNγ has been used in clinical trials for many cancer types. Studies in the bladder and ovarian carcinoma reported that the recombinant IFNγ significantly promotes T cell infiltration in the TME, which is beneficial for the prognosis of cancer patients.[119,120] Moreover, the administration of IFNγ inhibits cell growth and induces apoptosis in ovarian cancer cells. Several clinical trials of recombinant IFNγ have shown improved patient survival. Unfortunately, recombinant IFNγ also causes strong adverse effects, most patients suffer from “flu-like” symptoms (eg, chills, fever, headache) and some patients have symptoms such as diarrhea, nausea, and vomiting. In conclusion, some positive responses were observed after IFNγ treatment, but most studies failed due to considerable side effects. The cGAS-STING pathway plays an important role in antitumor immunity. Several trials have tested STING agonists as monotherapies or in combination with immunotherapies, including checkpoint inhibitors, cancer vaccine adjuvants, ICIs and chimeric antigen receptor T-cell (CAR-T) therapy. To date, the clinical trials based on the above strategies have not shown promising antitumor effects and remain to be evaluated carefully.
Overcoming impaired antitumor effects of IFNγ
Considering the limited efficacy of IFNγ-based therapy, more efforts have focused on developing new strategies to overcome the impaired IFNγ response of tumor cells. In recent years, the advent of ICB therapy has changed the original treatment paradigm for multiple cancer types and significantly improved the clinical efficacy in cancer patients. Mechanistically, immune checkpoint inhibitors (ICIs) restore the recognition and killing effect of the cytotoxic T cells mainly by blocking either the inhibitory receptor programmed cell death 1 (PD-1) on T cells or its ligand PD-L1 on tumor cells. To date, ICIs targeting the PD-L1/PD-1 axis have been approved for use in the clinic by the US Food and Drug Administration (FDA). Cancer cells with active IFNγ signaling are more likely to respond to ICB therapy. A transcriptomic analysis of baseline and on-therapy tumor biopsies from advanced melanomas treated with nivolumab (anti-PD1), alone or plus ipilimumab (anti-CTLA4), revealed an active IFNγ signaling signature as a biomarker of clinical response. Conversely, genomic defects in IFNγ signaling genes, such as IFNGR1/2, JAK1/2, and B2M, were observed in ICB-resistant tumors. Moreover, tumors that initially responded to PD-1 blockade became resistant after acquiring genetic alterations that inactivated JAK1/2. In addition, IFNγ-induced adaptive immune resistance remains a major obstacle in cancer immunotherapy over the past decade. A current study suggests that immunochemotherapy with IFNγ and dinaciclib, an inhibitor of cyclin-dependent kinase (CDK)-1, CDK2 and CDK5, overcomes IFNγ-triggered adaptive immune resistance and boosts an effective antitumor immune response in PDAC. Therefore, it is critical to monitor the dynamic changes in the IFNγ signaling pathway during the course of ICB treatment in cancer patients. It guides identifying responding patients and optimizing treatments during treatment.
Over the past years, our understanding of IFNγ production and its effects on cells has gone far beyond focusing on the classical JAK-STAT signaling pathway. Emerging evidence has demonstrated the important roles of epigenetic and metabolic regulation in IFNγ expression and function (Fig. 1). Furthermore, more research interests are not limited to exploring the role of IFNγ on immune cells, but focus on non-immune cells. It has been reported that IFNγ inhibits tumor cell proliferation and promotes various types of cell death. In addition, its regulatory effects on stromal cells further strengthen the antitumor effects of IFNγ. Given that all nucleated cells can respond to IFNγ, the functional consequences of IFNγ production need to be carefully dissected on a cell-by-cell basis (Fig. 2).
It is not surprising that IFNγ plays important homeostatic roles in both tumor immune surveillance and immune evasion. The balance of activating and inhibitory mechanisms of IFNγ determines the overall functional outcome. Cancer cells develop defensive strategies against IFNγ-induced immune surveillance, including induction of immunosuppressive factors and nutrient competition. In addition, some tumor cells exhibit hypo-responsiveness to IFNγ, which is mainly associated with a gene mutation or abnormal activation of cellular signaling (Fig. 3). So far, overcoming primary resistance, or acquired resistance after long-term treatment remains a great clinical challenge. Thus, further exploration of the regulatory mechanism of IFNγ will help us develop new therapeutic strategies to maintain the antitumor activity of IFNγ and overcome the resistance of cancer patients to currently available therapies.
YC collected the literature, wrote the manuscript; NN and JX revised the manuscript, and JX provided the overall guidance. All authors approved the final version of the manuscript.
This work was supported by the National Natural Science Foundation of China (No. 82022049, JX; No. 82073105, NN), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (No. 20161312, JX), State Key Laboratory of Oncogenes and Related Genes (KF2113, NN).
Conflicts of interest
The authors declare no conflicts of interest.
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