Pub Date : 2025-10-16DOI: 10.1016/j.smim.2025.101999
J. Alejandra Rodriguez, Humayra Habib, Matthew R. Olson
T helper 9 (Th9) cells, characterized by their production of interleukin-9 (IL-9), play pivotal roles in protective immunity and inflammatory disease. Their differentiation depends on the integration of three signals: TCR engagement (Signal 1), co-stimulatory receptor activation (Signal 2), and cytokine-driven transcriptional programming (Signal 3). This review explores how these signals converge to shape Th9 identity, highlighting the unique requirement for strong TCR signaling, heightened sensitivity to NF-κB signaling pathways, and the interplay of cytokine/STAT proteins. Understanding these mechanisms offers insights into Th9 biology and therapeutic strategies for cancer, allergy, and autoimmune disease.
{"title":"Three’s company: The cooperative signals behind the differentiation of Th9 cells","authors":"J. Alejandra Rodriguez, Humayra Habib, Matthew R. Olson","doi":"10.1016/j.smim.2025.101999","DOIUrl":"10.1016/j.smim.2025.101999","url":null,"abstract":"<div><div>T helper 9 (Th9) cells, characterized by their production of interleukin-9 (IL-9), play pivotal roles in protective immunity and inflammatory disease. Their differentiation depends on the integration of three signals: TCR engagement (Signal 1), co-stimulatory receptor activation (Signal 2), and cytokine-driven transcriptional programming (Signal 3). This review explores how these signals converge to shape Th9 identity, highlighting the unique requirement for strong TCR signaling, heightened sensitivity to NF-κB signaling pathways, and the interplay of cytokine/STAT proteins. Understanding these mechanisms offers insights into Th9 biology and therapeutic strategies for cancer, allergy, and autoimmune disease.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"80 ","pages":"Article 101999"},"PeriodicalIF":7.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1016/j.smim.2025.101997
Shima Sepehri-Manesh , Marion Debeaud , Valerie Vouret-Craviari
The IL-1 family comprises 11 cytokines, including IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-18, IL-33, and IL-36 cytokines to IL-37 and IL-38, that modulate innate immune system activity. In addition to their role in innate immunity, IL-1 family members can activate and enhance the function of polarized T cells. For example, IL-33 primarily influences T helper 2 (TH2) cells, IL-1 plays a central role in the differentiation of TH17 cells, and IL-18 predominantly affects TH1 cells. The IL-1 family members participated in various biological functions as described elsewhere in this special issue. Here, we provide an overview on IL-18, originally called IFN-γ inducing factor, and its role in impacting cancer immunity.
{"title":"Unlocking IL-18: A hidden key in cancer immunity","authors":"Shima Sepehri-Manesh , Marion Debeaud , Valerie Vouret-Craviari","doi":"10.1016/j.smim.2025.101997","DOIUrl":"10.1016/j.smim.2025.101997","url":null,"abstract":"<div><div>The IL-1 family comprises 11 cytokines, including IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-18, IL-33, and IL-36 cytokines to IL-37 and IL-38, that modulate innate immune system activity. In addition to their role in innate immunity, IL-1 family members can activate and enhance the function of polarized T cells. For example, IL-33 primarily influences T helper 2 (T<sub>H</sub>2) cells, IL-1 plays a central role in the differentiation of T<sub>H</sub>17 cells, and IL-18 predominantly affects T<sub>H</sub>1 cells. The IL-1 family members participated in various biological functions as described elsewhere in this special issue. Here, we provide an overview on IL-18, originally called IFN-γ inducing factor, and its role in impacting cancer immunity.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"80 ","pages":"Article 101997"},"PeriodicalIF":7.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-30DOI: 10.1016/j.smim.2025.101995
Negar Sharifi , Amir Emamie , Nastaran Rafiee , Salar Pashangzadeh , Eknoor Walia , Nikolas Tim Martin , Huy-Dung Hoang , Xiao Xiang , Tommy Alain
Reovirus is one of the most clinically investigated oncolytic viruses, with over 50 clinical trials and more than 1700 patients treated to date. Although it has yet to achieve complete regulatory approval, reovirus remains a promising oncolytic virus candidate for cancer immunotherapy due to its preferential replication in malignant cells, minimal toxicity in normal tissues, availability to be delivered via multiple routes, and strong immunostimulatory properties. As a non-enveloped, double-stranded RNA virus of the Reoviridae family, reovirus is typically asymptomatic in healthy individuals unlike its pathogenic relative, rotavirus, thus making it especially attractive for clinical use. Recent research has significantly expanded its therapeutic potential beyond direct oncolysis, highlighting its ability to remodel the tumor microenvironment, activate both innate and adaptive immunity, and synergize with chemotherapy, radiotherapy, and immune checkpoint inhibitors. Moreover, advances in oral delivery, nanoparticle encapsulation, mesenchymal stem cell-mediated transport, and genetic engineering, have further enhanced its safety, targeting precision, and therapeutic efficacy. This review summarizes recent breakthroughs in reovirus-based virotherapy and explores emerging strategies that may unlock its full potential as a next-generation immunotherapeutic platform.
{"title":"Reovirus oncolysis and the next frontiers for this unique oncoviral immunotherapy","authors":"Negar Sharifi , Amir Emamie , Nastaran Rafiee , Salar Pashangzadeh , Eknoor Walia , Nikolas Tim Martin , Huy-Dung Hoang , Xiao Xiang , Tommy Alain","doi":"10.1016/j.smim.2025.101995","DOIUrl":"10.1016/j.smim.2025.101995","url":null,"abstract":"<div><div>Reovirus is one of the most clinically investigated oncolytic viruses, with over 50 clinical trials and more than 1700 patients treated to date. Although it has yet to achieve complete regulatory approval, reovirus remains a promising oncolytic virus candidate for cancer immunotherapy due to its preferential replication in malignant cells, minimal toxicity in normal tissues, availability to be delivered via multiple routes, and strong immunostimulatory properties. As a non-enveloped, double-stranded RNA virus of the <em>Reoviridae</em> family, reovirus is typically asymptomatic in healthy individuals unlike its pathogenic relative, rotavirus, thus making it especially attractive for clinical use. Recent research has significantly expanded its therapeutic potential beyond direct oncolysis, highlighting its ability to remodel the tumor microenvironment, activate both innate and adaptive immunity, and synergize with chemotherapy, radiotherapy, and immune checkpoint inhibitors. Moreover, advances in oral delivery, nanoparticle encapsulation, mesenchymal stem cell-mediated transport, and genetic engineering, have further enhanced its safety, targeting precision, and therapeutic efficacy. This review summarizes recent breakthroughs in reovirus-based virotherapy and explores emerging strategies that may unlock its full potential as a next-generation immunotherapeutic platform.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"80 ","pages":"Article 101995"},"PeriodicalIF":7.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-29DOI: 10.1016/j.smim.2025.101996
Manuela Lizarralde-Guerrero , David Olagnier , Fernando Aranda , Maria Chiara Maiuri , Guido Kroemer , Jonathan G. Pol
Vesicular stomatitis virus (VSV), a rhabdovirus with intrinsic oncolytic properties, has emerged as a promising candidate for cancer therapy. Thanks to impaired antiviral responses affecting cancer cells, particularly downregulated type I interferon signaling, VSV selectively replicates in tumor cells while sparing normal cells. To mitigate neurotoxicity and improve therapeutic efficacy, genetically-engineered strains, such as VSV-∆M51, VSV-mIFNβ, and VSV-GP, have been developed. This review highlights the latest advances in VSV-based oncolytic virotherapy, focusing on novel modifications of the viral genome, as well as on combination strategies designed to enhance tumor selectivity, stimulate antitumor responses, and overcome resistance mechanisms. Recent studies have introduced modifications that bolster immunogenicity, and improve viral replication within tumors. Additionally, approaches combining VSV with small molecules, immune checkpoint inhibitors and other immunomodulatory agents, promise to augment antitumor activity. Emerging evidence suggests that VSV can reshape the tumor microenvironment, thus promoting robust adaptive antitumor immune responses. Ongoing research continues to explore strategies for improving systemic delivery, minimizing off-target effects, and enhancing viral persistence within the tumor bed. Further investigation and clinical translation will determine the full potential of VSV-based viroimmunotherapy in cancer treatment.
{"title":"Latest insights into oncolytic viro-immunotherapy with vesicular stomatitis virus","authors":"Manuela Lizarralde-Guerrero , David Olagnier , Fernando Aranda , Maria Chiara Maiuri , Guido Kroemer , Jonathan G. Pol","doi":"10.1016/j.smim.2025.101996","DOIUrl":"10.1016/j.smim.2025.101996","url":null,"abstract":"<div><div>Vesicular stomatitis virus (VSV), a rhabdovirus with intrinsic oncolytic properties, has emerged as a promising candidate for cancer therapy. Thanks to impaired antiviral responses affecting cancer cells, particularly downregulated type I interferon signaling, VSV selectively replicates in tumor cells while sparing normal cells. To mitigate neurotoxicity and improve therapeutic efficacy, genetically-engineered strains, such as VSV-∆M51, VSV-mIFNβ, and VSV-GP, have been developed. This review highlights the latest advances in VSV-based oncolytic virotherapy, focusing on novel modifications of the viral genome, as well as on combination strategies designed to enhance tumor selectivity, stimulate antitumor responses, and overcome resistance mechanisms. Recent studies have introduced modifications that bolster immunogenicity, and improve viral replication within tumors. Additionally, approaches combining VSV with small molecules, immune checkpoint inhibitors and other immunomodulatory agents, promise to augment antitumor activity. Emerging evidence suggests that VSV can reshape the tumor microenvironment, thus promoting robust adaptive antitumor immune responses. Ongoing research continues to explore strategies for improving systemic delivery, minimizing off-target effects, and enhancing viral persistence within the tumor bed. Further investigation and clinical translation will determine the full potential of VSV-based viroimmunotherapy in cancer treatment.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"80 ","pages":"Article 101996"},"PeriodicalIF":7.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1016/j.smim.2025.101994
Christoph F. Kollmann , Nadine van Montfoort , Pierre Cordelier , Jonathan Pol , David Olagnier
Oncolytic virotherapy (OVT) is a novel approach to cancer treatment that utilizes viruses to infect and destroy tumor cells selectively. Beyond direct oncolysis, OVT significantly reshapes the tumor microenvironment (TME), activating the adaptive immune system to generate robust and durable anti-tumor immunity. This review examines the diverse mechanisms by which OVT modulates the TME, including physical remodeling, alterations in cellular composition, and the induction of immunogenic cell death, which releases antigens and adjuvants that enhance immune activation. We also explore the synergistic effects of combining OVT with immune checkpoint inhibitors to counteract the immunosuppressive TME. Additionally, recent clinical studies are highlighted, demonstrating the transition of 'cold' tumors to 'hot' tumors and the establishment of systemic tumor control in patients treated with OVT. By enhancing TME immunogenicity, OVT emerges as a potent adjunct to anti-tumor immunotherapies, offering new opportunities to overcome resistance and achieve better therapeutic outcomes.
{"title":"Oncolytic virotherapy: Sparking durable anti-tumor immunity through microenvironment modulation","authors":"Christoph F. Kollmann , Nadine van Montfoort , Pierre Cordelier , Jonathan Pol , David Olagnier","doi":"10.1016/j.smim.2025.101994","DOIUrl":"10.1016/j.smim.2025.101994","url":null,"abstract":"<div><div>Oncolytic virotherapy (OVT) is a novel approach to cancer treatment that utilizes viruses to infect and destroy tumor cells selectively. Beyond direct oncolysis, OVT significantly reshapes the tumor microenvironment (TME), activating the adaptive immune system to generate robust and durable anti-tumor immunity. This review examines the diverse mechanisms by which OVT modulates the TME, including physical remodeling, alterations in cellular composition, and the induction of immunogenic cell death, which releases antigens and adjuvants that enhance immune activation. We also explore the synergistic effects of combining OVT with immune checkpoint inhibitors to counteract the immunosuppressive TME. Additionally, recent clinical studies are highlighted, demonstrating the transition of 'cold' tumors to 'hot' tumors and the establishment of systemic tumor control in patients treated with OVT. By enhancing TME immunogenicity, OVT emerges as a potent adjunct to anti-tumor immunotherapies, offering new opportunities to overcome resistance and achieve better therapeutic outcomes.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"80 ","pages":"Article 101994"},"PeriodicalIF":7.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2025-08-07DOI: 10.1016/j.smim.2025.101982
Alberto Caminero, Elisa Sánchez-Martínez, Mark Wulczynski, Lucía Moreno-Serna, Elena F Verdu, Rodrigo Jiménez-Saiz
Approximately 20 % of the global population reports adverse reactions to foods, with food allergy and celiac disease being the most well-characterized conditions. Although they involve distinct pathological mechanisms, both are recognized as antigen-driven immune disorders and potentially sharing unidentified genetic and environmental factors. The prevalence of food allergy and celiac disease has increased over the past few decades, a trend that cannot be explained solely by genetic changes. Recent clinical and experimental research indicates that infections and microbial agents play significant roles in disease initiation and progression through various mechanisms. Understanding these microbially-mediated processes could pave the way for preventive and therapeutic strategies for affected individuals and those at risk. In this narrative review, we comment on the potential role of microbes in these diseases, as well as their therapeutic implications.
{"title":"Potential role of microbes in antigen-based food sensitivities.","authors":"Alberto Caminero, Elisa Sánchez-Martínez, Mark Wulczynski, Lucía Moreno-Serna, Elena F Verdu, Rodrigo Jiménez-Saiz","doi":"10.1016/j.smim.2025.101982","DOIUrl":"10.1016/j.smim.2025.101982","url":null,"abstract":"<p><p>Approximately 20 % of the global population reports adverse reactions to foods, with food allergy and celiac disease being the most well-characterized conditions. Although they involve distinct pathological mechanisms, both are recognized as antigen-driven immune disorders and potentially sharing unidentified genetic and environmental factors. The prevalence of food allergy and celiac disease has increased over the past few decades, a trend that cannot be explained solely by genetic changes. Recent clinical and experimental research indicates that infections and microbial agents play significant roles in disease initiation and progression through various mechanisms. Understanding these microbially-mediated processes could pave the way for preventive and therapeutic strategies for affected individuals and those at risk. In this narrative review, we comment on the potential role of microbes in these diseases, as well as their therapeutic implications.</p>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"79 ","pages":"101982"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-30DOI: 10.1016/j.smim.2025.101984
Valérie Abadie
The intestinal mucosa employs a diverse set of defense mechanisms—from mucosal barrier regulation to immunoregulatory pathways—to maintain homeostasis despite constant exposure to microbial and dietary antigens. Failure to establish immune tolerance to food antigens can lead to pathological conditions such as celiac disease (CeD) and food allergies. This review provides an overview of the sequential processes that support tolerance to food antigens and examines how gene-environment interactions contribute to the pathogenesis of CeD and food allergies. Although the exact nature of the environmental triggers is unknown, microbial agents - whether bacterial or viral- are believed to play a critical role in disrupting homeostatic mechanisms in genetically predisposed individuals. Tolerogenic responses to dietary antigens can be compromised by environmentally induced local inflammation or epithelial barrier disruption, leading to the expansion of T helper 1 (TH1) responses in CeD and TH2 responses in food allergies. This divergence in immune activation across distinct mucosal sites underscores the unique immunopathogenesis of CeD and food allergies—conditions for which our understanding has grown significantly, yet effective interventions remain limited.
{"title":"Gut mucosal immune responses – Implications for celiac disease and food allergy","authors":"Valérie Abadie","doi":"10.1016/j.smim.2025.101984","DOIUrl":"10.1016/j.smim.2025.101984","url":null,"abstract":"<div><div>The intestinal mucosa employs a diverse set of defense mechanisms—from mucosal barrier regulation to immunoregulatory pathways—to maintain homeostasis despite constant exposure to microbial and dietary antigens. Failure to establish immune tolerance to food antigens can lead to pathological conditions such as celiac disease (CeD) and food allergies. This review provides an overview of the sequential processes that support tolerance to food antigens and examines how gene-environment interactions contribute to the pathogenesis of CeD and food allergies. Although the exact nature of the environmental triggers is unknown, microbial agents - whether bacterial or viral- are believed to play a critical role in disrupting homeostatic mechanisms in genetically predisposed individuals. Tolerogenic responses to dietary antigens can be compromised by environmentally induced local inflammation or epithelial barrier disruption, leading to the expansion of T helper 1 (T<sub>H</sub>1) responses in CeD and T<sub>H</sub>2 responses in food allergies. This divergence in immune activation across distinct mucosal sites underscores the unique immunopathogenesis of CeD and food allergies—conditions for which our understanding has grown significantly, yet effective interventions remain limited.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"80 ","pages":"Article 101984"},"PeriodicalIF":7.8,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-28DOI: 10.1016/j.smim.2025.101983
Camillo Bechi Genzano , Tyla Young , Rachel Bonami , Raniero Chimienti , Leonardo M.R. Ferreira , Emily K. Sims , Remi J. Creusot
In Type 1 diabetes (T1D), pancreatic β cells are progressively lost, resulting in insulin insufficiency. Although exogenous insulin is essential for disease management, it is not a cure, and inadequate glycemic control continues to result in long-term complications. Thus, there is a need for therapies that address the underlying autoimmune response, a key component of T1D pathogenesis. This review examines a wide range of actionable immunomodulatory targets at the tissue, cellular, and molecular levels that form the basis of current and emerging therapies for T1D. Particular emphasis is placed on T cell populations, which play a central role; with other immune cell types contributing to varying degrees also discussed. Immune-modifying therapies aim to prevent or reverse the pathogenic functions of these cells, including their interactions with β cells. Many of these approaches are directed at specific immune cell populations, but not only the pathogenic ones. Recent advances have enabled more precise targeting, based on tissue relevance or antigen specificity. The immune system may also be indirectly modulated by targeting the microbiome, offering potential new strategies for early prevention of T1D. Many of these targets were identified from animal models and remain to be validated in humans, leaving numerous therapeutic avenues open for exploration.
{"title":"Autoimmune diabetes and targets for immunomodulation","authors":"Camillo Bechi Genzano , Tyla Young , Rachel Bonami , Raniero Chimienti , Leonardo M.R. Ferreira , Emily K. Sims , Remi J. Creusot","doi":"10.1016/j.smim.2025.101983","DOIUrl":"10.1016/j.smim.2025.101983","url":null,"abstract":"<div><div>In Type 1 diabetes (T1D), pancreatic β cells are progressively lost, resulting in insulin insufficiency. Although exogenous insulin is essential for disease management, it is not a cure, and inadequate glycemic control continues to result in long-term complications. Thus, there is a need for therapies that address the underlying autoimmune response, a key component of T1D pathogenesis. This review examines a wide range of actionable immunomodulatory targets at the tissue, cellular, and molecular levels that form the basis of current and emerging therapies for T1D. Particular emphasis is placed on T cell populations, which play a central role; with other immune cell types contributing to varying degrees also discussed. Immune-modifying therapies aim to prevent or reverse the pathogenic functions of these cells, including their interactions with β cells. Many of these approaches are directed at specific immune cell populations, but not only the pathogenic ones. Recent advances have enabled more precise targeting, based on tissue relevance or antigen specificity. The immune system may also be indirectly modulated by targeting the microbiome, offering potential new strategies for early prevention of T1D. Many of these targets were identified from animal models and remain to be validated in humans, leaving numerous therapeutic avenues open for exploration.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"79 ","pages":"Article 101983"},"PeriodicalIF":7.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-15DOI: 10.1016/j.smim.2025.101981
Rachel Weissman-Tsukamoto, Kaitlin R. Carroll, Betty Diamond
Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) occur in more than half of patients with SLE, with symptoms including fatigue, anxiety, depression, pain, psychosis, and cognitive dysfunction. These symptoms are often present at the time of diagnosis of SLE and can be insidious. Patients consider these to be among their most debilitating symptoms which most diminish their quality of life, but recognition and attribution of these frequently non-acute symptoms can be difficult, resulting in underassessment, underdiagnosis, and poor understanding of the underlying pathogenic mechanisms and how to treat them. In this review, we highlight findings from neuroimaging studies which have been critical in proving the existence of structural and functional brain alterations that associate with symptomatology, and pathophysiological findings from animal models of diffuse NPSLE, focusing principally on blood brain barrier injury and brain-reactive autoantibodies. Most importantly, we demonstrate that mechanistic progress can be made with respect to these manifestations of NPSLE and that this progress leads to therapeutic strategies which can be tested in clinical trials.
{"title":"Diffuse neuropsychiatric lupus: Clinical evidence, immune-mediated mechanisms, and therapeutic insights","authors":"Rachel Weissman-Tsukamoto, Kaitlin R. Carroll, Betty Diamond","doi":"10.1016/j.smim.2025.101981","DOIUrl":"10.1016/j.smim.2025.101981","url":null,"abstract":"<div><div>Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) occur in more than half of patients with SLE, with symptoms including fatigue, anxiety, depression, pain, psychosis, and cognitive dysfunction. These symptoms are often present at the time of diagnosis of SLE and can be insidious. Patients consider these to be among their most debilitating symptoms which most diminish their quality of life, but recognition and attribution of these frequently non-acute symptoms can be difficult, resulting in underassessment, underdiagnosis, and poor understanding of the underlying pathogenic mechanisms and how to treat them. In this review, we highlight findings from neuroimaging studies which have been critical in proving the existence of structural and functional brain alterations that associate with symptomatology, and pathophysiological findings from animal models of diffuse NPSLE, focusing principally on blood brain barrier injury and brain-reactive autoantibodies. Most importantly, we demonstrate that mechanistic progress can be made with respect to these manifestations of NPSLE and that this progress leads to therapeutic strategies which can be tested in clinical trials.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"79 ","pages":"Article 101981"},"PeriodicalIF":7.8,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-29DOI: 10.1016/j.smim.2025.101980
Maite G. Fernandez-Barrena , Iker Uriarte , Pablo Sarobe , Matias A. Avila
Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor and is currently a major cause of cancer-related mortality worldwide. The arrival of immune checkpoint inhibitors (ICI), and their combination with anti-VEGF/VEGFR antibodies, has transformed the treatment of patients with advanced HCC. Still, only about 30 % of patients respond to therapy, and these cases are among those displaying an immune-enriched (“immune-hot”) tumor microenvironment (TME). Therefore, the identification of combination strategies that can overcome ICI resistance is of high relevance. Epigenetic alterations are increasingly recognized to impact on tumor development, contributing to practically all the hallmarks of cancer. These mechanisms not only promote the growth and survival of cancer cells, also determine the phenotype of immune cells and other components of the TME, driving tumor progression and resistance to therapies. Emerging preclinical evidence in different tumor types indicates that the combination with the so-called epi-drugs can increase the efficacy and overcome resistance to ICI. Here, we provide an overview of the epigenetic rewiring occurring in cancer and immune cells that can hinder antitumor immunity and ICI’s efficacy in HCC. We also discuss how epigenetically targeted therapies may be leveraged to synergize with ICI and potentially treat immune-cold HCCs.
{"title":"Epigenetic mechanisms in HCC immune landscape: Therapeutic implications","authors":"Maite G. Fernandez-Barrena , Iker Uriarte , Pablo Sarobe , Matias A. Avila","doi":"10.1016/j.smim.2025.101980","DOIUrl":"10.1016/j.smim.2025.101980","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor and is currently a major cause of cancer-related mortality worldwide. The arrival of immune checkpoint inhibitors (ICI), and their combination with anti-VEGF/VEGFR antibodies, has transformed the treatment of patients with advanced HCC. Still, only about 30 % of patients respond to therapy, and these cases are among those displaying an immune-enriched (“immune-hot”) tumor microenvironment (TME). Therefore, the identification of combination strategies that can overcome ICI resistance is of high relevance. Epigenetic alterations are increasingly recognized to impact on tumor development, contributing to practically all the hallmarks of cancer. These mechanisms not only promote the growth and survival of cancer cells, also determine the phenotype of immune cells and other components of the TME, driving tumor progression and resistance to therapies. Emerging preclinical evidence in different tumor types indicates that the combination with the so-called epi-drugs can increase the efficacy and overcome resistance to ICI. Here, we provide an overview of the epigenetic rewiring occurring in cancer and immune cells that can hinder antitumor immunity and ICI’s efficacy in HCC. We also discuss how epigenetically targeted therapies may be leveraged to synergize with ICI and potentially treat immune-cold HCCs.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"79 ","pages":"Article 101980"},"PeriodicalIF":7.8,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144721514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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