IFNα Subtypes in HIV Infection and Immunity.

Type I interferons (IFN), immediately triggered following most viral infections, play a pivotal role in direct antiviral immunity and act as a bridge between innate and adaptive immune responses. However, numerous viruses have evolved evasion strategies against IFN responses, prompting the exploration of therapeutic alternatives for viral infections. Within the type I IFN family, 12 IFNα subtypes exist, all binding to the same receptor but displaying significant variations in their biological activities. Currently, clinical treatments for chronic virus infections predominantly rely on a single IFNα subtype (IFNα2a/b). However, the efficacy of this therapeutic treatment is relatively limited, particularly in the context of Human Immunodeficiency Virus (HIV) infection. Recent investigations have delved into alternative IFNα subtypes, identifying certain subtypes as highly potent, and their antiviral and immunomodulatory properties have been extensively characterized. This review consolidates recent findings on the roles of individual IFNα subtypes during HIV and Simian Immunodeficiency Virus (SIV) infections. It encompasses their induction in the context of HIV/SIV infection, their antiretroviral activity, and the diverse regulation of the immune response against HIV by distinct IFNα subtypes. These insights may pave the way for innovative strategies in HIV cure or functional cure studies.

A cluster of type I interferon-regulated genes associates with disease activity and prognosis in patients with IgA nephropathy.

The exact pathogenesis of IgA nephropathy (IgAN) is complex and so far, not well defined. Since it has been shown that microbial infections could induce high levels of type I interferon (IFN-I) and there is an evident link between mucosal infection and gross hematuria in IgAN, we hypothesized that IFN-I may play a role in the pathogenic process. In this study, we investigated the type I interferon status in IgAN based on the expression of 17 IFN-regulated genes (IRGs) in whole blood from 59 IgAN patients in a cross-sectional study, of which 34 patients followed longitudinally. Analysis of the IFN-score showed that there was a significant elevated IFN-score in the IgAN patients compared with healthy controls (n = 28, p = 9.80 × 10-3), and we observed an elevated IFN-score in the group with less tubular atrophy/interstitial fibrosis (p = 1.07 × 10-2) and with a lower proportion of mesangial hypercellularity (p = 1.23 × 10-2). In the longitudinal analysis, Cox regression analysis revealed that a higher IFN level was associated with a better renal outcome in IgAN after adjustments for gender and age (hazard ratio, 0.90; 95 % confidence interval, 0.81 to 0.97; p = 4.20 × 10-2). In conclusion, our finding suggested that IFN score may represent a novel type of biomarker in IgAN, which requires further exploration on its mechanism and therapeutic targeting.

The tumor cell-intrinsic cGAS-STING pathway is associated with the high density of CD8+ T cells after chemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Chemotherapy has the potential to induce CD8+ T-cell infiltration in the tumor microenvironment (TME) and activate the anti-tumor immune response in several cancers including esophageal squamous cell carcinoma (ESCC). The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been known as a critical component for regulating immune cell activation in the TME. However, its effect on the infiltration of immune cells induced by chemotherapy in the ESCC TME has not been investigated. METHODS: We examined the effect of the tumor-cell intrinsic cGAS-STING pathway on the infiltration of CD8+ T cells induced by chemotherapy in ESCC using ESCC cell lines and surgically resected ESCC specimens from patients who received neoadjuvant chemotherapy (NAC). RESULTS: We found that chemotherapeutic agents, including 5-fluorouracil (5-FU) and cisplatin (CDDP), activated the cGAS-STING pathway, consequently inducing the expression of type I interferon and T-cell-attracting chemokines in ESCC cells. Moreover, the tumor cell-intrinsic expression of cGAS-STING was significantly and positively associated with the density of CD8+ T cells in ESCC after NAC. However, the tumor cell-intrinsic expression of cGAS-STING did not significantly impact clinical outcomes in patients with ESCC after NAC. CONCLUSION: Our findings suggest that the tumor cell-intrinsic cGAS-STING pathway might contribute to chemotherapy-induced immune cell activation in the ESCC TME.

Fufang Luohanguo Qingfei granules reduces influenza virus susceptibility via MAVS-dependent type I interferon antiviral signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Luohanguo Qingfei granules (LQG) is a Chinese patent medicine, clinically used to treat flu-like symptoms including cough with yellow phlegm, impeded phlegm, dry throat and tongue. However, the protective activity of LQG against influenza infection is indeterminate. AIM OF THE STUDY: This study is to investigate the therapeutic effect of LQG on influenza infection and elucidate its underlying mechanism. MATERIALS AND METHODS: In vivo: A viral susceptible mouse model induced by restraint stress was established to investigate LQG's beneficial effects on influenza susceptibility. MAVS knockout (Mavs-/-) mice were used to verify the potential mechanism of LQG. In vitro: Corticosteroid (CORT)-treated A549 cells were employed to identify the active ingredients in LQG. Mice morbidity and mortality were monitored daily for 21 days. Histopathologic changes and inflammatory cytokines in lung tissues were examined by H&E staining and ELISA. RNA-seq was used to explore the signaling pathway influenced by LQG and further confirmed by qPCR. Immunoblotting and immunohistochemistry (IHC) were used to determine the protein levels. CO-IP and DARTS were applied to detect protein-protein interaction and compound-protein interaction, respectively. RESULTS: LQG effectively attenuated the susceptibility of restrained mice to H1N1 infection. LQG significantly boosted the production of IFN-ß transduced by mitochondrial antiviral-signaling protein (MAVS), while MAVS deficiency abrogated its protective effects on restrained mice infected with H1N1. Moreover, in vitro studies further revealed that mogroside Ⅱ B, amygdalin, and luteolin are potentially active components of LQG. CONCLUSION: These results suggested that LQG inhibited the mitofusin 2 (Mfn2)-mediated ubiquitination of MAVS by impeding the E3 ligase synoviolin 1 (SYVN1) recruitment, thereby enhancing IFN-ß antiviral response. Overall, our work elaborates a potential regimen for influenza treatment through reduction of stress-induced susceptibility.

Type I and type III interferons: From basic biology and genetics to clinical development for COVID-19 and beyond.

Type I and type III interferons (IFNs) constitute a key antiviral defense systems of the body, inducing viral resistance to cells and mediating diverse innate and adaptive immune functions. Defective type I and type III IFN responses have recently emerged as the 'Achilles heel' in COVID-19, with such patients developing severe disease and exhibiting a high risk for critical pneumonia and death. Here, we review the biology of type I and type III IFNs, their similarities and important functional differences, and their roles in SARS-CoV-2 infection. We also appraise the various mechanisms proposed to drive defective IFN responses in COVID-19 with particular emphasis to the ability of SARS-CoV-2 to suppress IFN production and activities, the genetic factors involved and the presence of autoantibodies neutralizing IFNs and accounting for a large proportion of individuals with severe COVID-19. Finally, we discuss the long history of the type I IFN therapeutics for the treatment of viral diseases, cancer and multiple sclerosis, the various efforts to use them in respiratory infections, and the newly emerging type III IFN therapeutics, with emphasis to the more recent studies on COVID-19 and their potential use as broad spectrum antivirals for future epidemics or pandemics.

The type-I interferon response potentiates seeded tau aggregation and exacerbates tau pathology.

INTRODUCTION: Signatures of a type-I interferon (IFN-I) response are observed in the post mortem brain in Alzheimer's disease (AD) and other tauopathies. However, the effect of the IFN-I response on pathological tau accumulation remains unclear. METHODS: We examined the effects of IFN-I signaling in primary neural culture models of seeded tau aggregation and P301S-tau transgenic mouse models in the context of genetic deletion of the IFN-I receptor (IFNAR). RESULTS: Polyinosinic:polycytidylic acid (PolyI:C), a synthetic analog of viral nucleic acids, evoked a potent cytokine response that enhanced seeded aggregation of tau in an IFN-I-dependent manner. IFN-I-induced vulnerability could be pharmacologically prevented and was intrinsic to neurons. Aged P301S-tau mice lacking Ifnar1 had significantly reduced tau pathology compared to mice with intact IFN signaling. DISCUSSION: We identify a critical role for IFN-I in potentiating tau aggregation. IFN-I is therefore identified as a potential therapeutic target in AD and other tauopathies. HIGHLIGHTS: Type-I IFN (IFN-I) promotes seeded tau aggregation in neural cultures. IFNAR inhibition prevents IFN-I driven sensitivity to tau aggregation. IFN-I driven vulnerability is intrinsic to neurons. Tau pathology is significantly reduced in aged P301S-tau mice lacking IFNAR.

Type 1 interferons: A target for immune-mediated inflammatory diseases (IMIDs).

The improved understanding of the molecular basis of innate immunity have led to the identification of type I interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of several Immune-mediated inflammatory diseases (IMIDs) such as systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis and Sjögren's syndrome. Here, we review the main data regarding the opportunity to target type I IFNs for the treatment of IMIDs. Type I IFNs and their downstream pathways can be targeted pharmacologically in several manners. One approach is to use monoclonal antibodies against IFNs or the IFN-receptors (IFNARs, such as with anifrolumab). The downstream signaling pathways of type I IFNs also contain several targets of interest in IMIDs, such as JAK1 and Tyk2. Of these, anifrolumab is licensed and JAK1/Tyk2 inhibitors are in phase III trials in SLE. Targeting IFN-Is for the treatment of SLE is already a reality and in the near future may prove useful in other IMIDs. IFN assays will find a role in routine clinical practice for the care of IMIDs as further validation work is completed and a greater range of targeted therapies becomes available.

Combining PD-1/PD-L1 blockade with type I interferon in cancer therapy.

PD-1 and PD-L1 are crucial regulators of immunity expressed on the surface of T cells and tumour cells, respectively. Cancer cells frequently use PD-1/PD-L1 to evade immune detection; hence, blocking them exposes tumours to be attacked by activated T cells. The synergy of PD-1/PD-L1 blockade with type I interferon (IFN) can improve cancer treatment efficacy. Type I IFN activates immune cells boosts antigen presentation and controls proliferation. In addition, type I IFN increases tumour cell sensitivity to the blockade. Combining the two therapies increases tumoral T cell infiltration and activation within tumours, and stimulate the generation of memory T cells, leading to prolonged patient survival. However, limitations include heterogeneous responses, the need for biomarkers to predict and monitor outcomes, and adverse effects and toxicity. Although treatment resistance remains an obstacle, the combined therapeutic efficacy of IFNα/ß and PD-1/PD-L1 blockade demonstrated considerable benefits across a spectrum of cancer types, notably in melanoma. Overall, the phases I and II clinical trials have demonstrated safety and efficiency. In future, further investigations in clinical trials phases III and IV are essential to compare this combinatorial treatment with standard treatment and assess long-term side effects in patients.

Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response.

Type I interferon (IFN-I) is thought to play a role in many systemic autoimmune diseases. IFN-I pathway activation is associated with pathogenic features, including the presence of autoantibodies and clinical phenotypes such as more severe disease with increased disease activity and damage. We will review the role and potential drivers of IFN-I dysregulation in 5 prototypic autoimmune diseases: systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, primary Sjögren syndrome, and systemic sclerosis. We will also discuss current therapeutic strategies that directly or indirectly target the IFN-I system.

STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLC.

INTRODUCTION: Conflicting findings have been reported regarding the association between STK11/LKB1 mutations and immune checkpoint inhibitor (ICB) efficacy in NSCLC. It has been reported that tumors could exhibit impaired STK11/LKB1 function even without STK11 mutations. We hypothesized that STK11 phenotype rather than mutation may better stratify ICB outcomes. METHODS: Selected functional STK11 events and LKB1 protein data were leveraged to establish a transcriptomics-based classifier of STK11 phenotype (STK11-deficient [-def] or -proficient [-prof]). We analyzed in-house and Genentech/Roche's data of three randomized trials of programmed cell death protein-1 or programmed death-ligand 1 (PD-L1) inhibition in NSCLC (ORIENT-11, n = 171; OAK, n = 699; POPLAR, n = 192) and The Cancer Genome Atlas-NSCLC cohort. RESULTS: Tissue STK11 mutation did not affect ICB outcomes. However, the survival benefit of ICB versus chemotherapy were lost or reversed in STK11-def tumors (hazard ratios for death, 95% confidence interval: OAK [0.97, 0.69-1.35]; POPLAR [1.61, 0.88-2.97]; ORIENT-11 [1.07, 0.50-2.29]), while remaining in STK11-prof tumors (hazard ratios for death, 95% confidence interval: OAK [0.81, 0.66-0.99]; POPLAR [0.66, 0.46-0.95]; ORIENT-11 [0.59, 0.37-0.92]). In tumors differentially classified by phenotype and mutation status, STK11-wild-type/def tumors had significantly worse ICB outcomes than STK11-mutated (STK11-MUT)/prof tumors (p < 0.05). The deleterious impact of STK11 deficiency was independent of STK11/KRAS/KEAP1 status or PD-L1 expression. The STING/interferon-I signaling, which was previously shown to be suppressed in STK11-MUT models, was perturbed in patients with STK11-def tumors rather than those with STK11-MUT tumors. Surprisingly, whereas high CD8+ T-cell infiltration was significantly associated with prolonged survival with ICB in STK11-prof tumors (p < 0.05 for 3 trials), it predicted an opposite trend toward worse ICB outcomes in STK11-def tumors across three trials. This suggested an association between STK11 deficiency and CD8+ T-cell dysfunction, which might not be reversed by programmed cell death protein 1 or PD-L1 blockade. CONCLUSIONS: STK11 phenotype rather than mutation status can accurately identify patients with ICB-refractory NSCLC and reflect immune suppression. It can help refine stratification algorithms for future clinical research and also provide a reliable resource aiding basic and translational studies in identifying therapeutic targets.

The interferon in idiopathic inflammatory myopathies: Different signatures and new therapeutic perspectives. A literature review.

Idiopathic inflammatory myopathies (IIM), even though sharing common clinical manifestations, are characterized by diversified molecular pathogenetic mechanisms which may account for the partial inefficacy of currently used immunomodulatory drugs. In the last decades, the role of interferon (IFN) in IIM has been extensively elucidated thanks to genomic and proteomic studies which have assessed the molecular signature at the level of affected tissues or in peripheral blood across distinct IIM subtypes. A predominant type I IFN response has been shown in dermatomyositis (DM), being especially enhanced in anti-melanoma differentiation-associated gene 5 (MDA5)+ DM, while a type 2 IFN profile characterizes anti-synthetase syndrome (ASyS) and inclusion body myositis (IBM); conversely, a less robust IFN footprint has been defined for immune-mediated necrotizing myopathy (IMNM). Intracellular IFN signaling is mediated by the janus kinase/signal transducer and activator of transcription (JAK/STAT) through dedicated transmembrane receptors and specific cytoplasmic molecular combinations. These results may have therapeutic implications and led to evaluating the efficacy of new targeted drugs such as the recently introduced janus kinase inhibitors (JAKi), currently approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In this review we aim to summarize the most significant evidence of IFN role in IIM pathogenesis and to describe the current state of the art about the ongoing clinical trials on IFN-targeting drugs, with particular focus on JAKi.

Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication.

Dengue virus (DENV) infection can induce life-threatening dengue hemorrhagic fever/dengue shock syndrome in infected patients. DENV is a threat to global health due to its growing numbers and incidence of infection in the last 50 years. During infection, DENV expresses ten structural and nonstructural proteins modulating cell responses to benefit viral replication. However, the lack of knowledge regarding the cellular proteins and their functions in enhancing DENV pathogenesis impedes the development of antiviral drugs and therapies against fatal DENV infection. Here, we identified that integrin-linked kinase (ILK) is a novel enhancing factor for DENV infection by suppressing type I interferon (IFN) responses. Mechanistically, ILK binds DENV NS1 and NS3, activates Akt and Erk, and induces NF-κB-driven suppressor of cytokine signaling 3 (SOCS3) expression. Elevated SOCS3 in DENV-infected cells inhibits phosphorylation of STAT1/2 and expression of interferon-stimulated genes (ISGs). Inhibiting ILK, Akt, or Erk activation abrogates SOCS3 expression. In DENV-infected mice, the treatment of an ILK inhibitor significantly reduces viral loads in the brains, disease severity, and mortality rate. Collectively, our results show that ILK is a potential therapeutic target against DENV infection.

Emerging role for interferons in respiratory viral infections and childhood asthma.

Respiratory syncytial virus (RSV) and Rhinovirus (RV) infections are major triggers of severe lower respiratory illnesses (sLRI) in infants and children and are strongly associated with the subsequent development of asthma. Decades of research has focused on the role of type I interferons in antiviral immunity and ensuing airway diseases, however, recent findings have highlighted several novel aspects of the interferon response that merit further investigation. In this perspective, we discuss emerging roles of type I interferons in the pathogenesis of sLRI in children. We propose that variations in interferon response patterns exist as discrete endotypes, which operate locally in the airways and systemically through a lung-blood-bone marrow axis. We discuss new insights into the role of interferons in immune training, bacterial lysate immunotherapy, and allergen-specific immunotherapy. Interferons play complex and diverse roles in the pathogenesis of sLRI and later asthma, providing new directions for mechanistic studies and drug development.

Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance.

Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA-deficient tumors. However, over 40% of BRCA-deficient patients fail to respond to PARPi. Here, we report that thioparib, a next-generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1-dependent DNA damage and replication stress, causing S-phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR-mediated DNA repair while increasing RAD51 foci formation. Notably, the on-target inhibition of PARP7 by thioparib-activated STING/TBK1-dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome-scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next-generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier-generation PARPi.

Interferons and systemic lupus erythematosus: Pathogenesis, clinical features, and treatments in interferon-driven disease.

Type I interferons (IFNs) have recently received a lot of attention with the elucidation of the pathogenesis of systemic lupus erythematosus (SLE). Type I IFNs are associated with many SLE symptoms and play a role in the pathogenesis of autoimmune diseases that may occur concurrently with SLE, such as Sjögren's syndrome, antiphospholipid syndrome, myositis, scleroderma, and interferonopathy. Type I IFNs could be the link between these diseases. However, direct measurement of type I IFN levels and the IFN gene signature is currently unavailable in clinical practice. This review discusses type I IFN signalling in SLE, investigates the role of type I IFN in the clinical manifestations and symptoms associated with SLE and other IFN-related diseases, and discusses the clinical tests that can be used to diagnose SLE and measure disease activity. In addition, the role of type I IFN-blocking therapies as potential treatments for SLE is discussed.

Total glucosides of paeony alleviates scleroderma by inhibiting type I interferon responses.

ETHNOPHARMACOLOGICAL RELEVANCE: Type I interferon (IFN) is believed to play a pathogenic role in systemic sclerosis (SSc, also called scleroderma), which is an autoimmune rheumatic disease. Our previous studies have found that Chinese medicine formula Si-Ni-San (SNS, composed of Glycyrrhiza uralensis Fisch., Bupleurum chinense DC., Paeonia lactiflora Pall., and Citrus aurantium L.) had inhibitory effects on type I IFN responses. Among these herbal products, Paeonia lactiflora Pall. has been traditionally used to treat inflammation-related diseases, yet its therapeutic effects against type I IFN-related diseases and potential bioactive ingredients are not characterized. AIM OF THE STUDY: We aim to identify bioactive ingredient with anti-type I IFN activity from herbal products in SNS and further elucidate its therapeutic effect against scleroderma and underlying mechanisms. MATERIALS AND METHODS: We constructed a Gaussia-luciferase (Gluc) reporter assay system to identify ingredients with anti-type I IFN activities from SNS. In RAW264.7 cells, real-time PCR (RT-PCR) and western blotting were used to investigate the induction of type I IFN pathway. Additionally, in a bleomycin (BLM)-induced experimental scleroderma model, the expression of fibrotic genes, type I IFN-related genes, inflammatory cytokines, and cytotoxic granules were measured by RT-PCR, and the histopathological changes were determined by H&E staining, Masson's staining and immunohistochemistry analysis. RESULTS: Our data demonstrated that total glucosides of paeony (TGP) was the bioactive component of SNS that selectively inhibited TLR3-mediated type I IFN responses and blocked type I IFN-induced downstream JAK-STAT signaling pathways. In the BLM-induced scleroderma mouse model, TGP ameliorated skin fibrosis by inhibiting multiple targets in the upstream and downstream of type I IFN signaling. Further research found that TGP hindered polarization of M2 macrophages and their profibrotic effects and reduced cytotoxic T lymphocytes and their cytotoxic granules by suppressing Cxcl9 and Cxcl10 in the skin tissue of scleroderma mice. CONCLUSIONS: Our study not only sheds novel lights into the immunoregulative effects of TGP but also provides convincing evidence to develop TGP-based therapies in the treatment of scleroderma and other autoimmune diseases associated with type I IFN signatures. CLASSIFICATION: Skin.

What is new in the treatment of Systemic Lupus Erythematosus?

Systemic lupus erythematosus treatment is targeted to achieve remission or low disease activity and protection from disease flares. A number of immunosupresive drugs in combination with glucocorticoids are used for this purpose and there is an increased possibility of the use of biologic treatment, especially of belimumab. Calcineurin inhibitor voclosporin is a novelty in lupus nephritis treatment. Another novelty is anifrolumab, a biologic drug which inhibits the activity of type I interferons. An integral part of care is the prevention of late disease complications, especially cardiovascular risk management.

The convergence of tumor suppressors on the type I interferon pathway in clear cell renal cell carcinoma and its therapeutic implications.

In clear cell renal cell carcinoma (ccRCC), the von Hippel-Lindau tumor suppressor gene/hypoxia inducible factor (VHL/HIF) axis lays the groundwork for tumorigenesis and is the target of many therapeutic agents. HIF activation alone, however, is largely insufficient for kidney tumor development, and secondary mutations in PBRM1, BAP1, SETD2, KDM5C, or other tumor suppressor genes are strong enablers of tumorigenesis. Interestingly, it has been discovered that VHL loss and subsequent HIF activation results in upregulation of a negative feedback loop mediated by ISGF3, a transcription factor activated by type I interferon (IFN). Secondary mutations in the aforementioned tumor suppressor genes all partially disable this negative feedback loop to facilitate tumor growth. The convergence of several cancer genes on this pathway suggests that it plays an important role in ccRCC development and maintenance. Tumors with secondary mutations that dampen the negative feedback loop may be exquisitely sensitive to its reactivation, and pharmacological activation of ISGF3 either alone or in combination with other therapies could be an effective method to treat patients with ccRCC. In this review, we examine the relevance of the type I IFN pathway to ccRCC, synthesize our current knowledge of the ccRCC tumor suppressors in its regulation, and explore how this may impact the future treatment of patients with ccRCC.

Deucravacitinib for the Treatment of Psoriatic Disease.

Psoriasis is an immune-mediated disease, with the interleukin (IL)-23/IL-17 axis currently considered its main pathogenic pathway. Tyrosine kinase 2 (TYK2) is responsible for mediating immune signalling of IL-12, IL-23 and type I interferons, without interfering with other critical systemic functions as other JAK proteins do. This article aims to review the current knowledge on deucravacitinib, a new oral drug that selectively inhibits TYK2, granting it a low risk of off-target effects. After good efficacy and safety results in a phase II, placebo-controlled trial, two phase III, 52-week trials evaluated deucravacitinib 6 mg against placebo and apremilast-an active comparator. POETYK PSO-1 and PSO-2 involved 1688 patients with moderate-to-severe psoriasis. After 16 weeks, in both studies, over 50% of patients treated with deucravacitinib reached PASI75, which was significantly superior to placebo and apremilast. In POETYK PSO-1, these results improved until week 24 and were maintained through week 52, with over 65% of patients achieving PASI75 at this point. A reduction in signs and symptoms was also reported by patients, with greater impact on itch. Deucravacitinib was well tolerated and safe. There were no reports of serious infections, thromboembolic events, or laboratory abnormalities, which are a concern among other JAK inhibitors. Persistent efficacy and consistent safety profiles were reported for up to 2 years. Despite advances in the treatment of psoriasis, namely among biologic agents, an oral, effective and safe new drug can bring several advantages to prescribers and patients. Further investigation is required to understand where to place deucravacitinib among current psoriasis treatment options.