Sickle cell disease (SCD) is a severe monogenic red blood cell (RBC) disorder that follows a simple Mendelian mode of inheritance. SCD is characterized by hemoglobin S polymerization under deoxygenated conditions, leading to chronic hemolysis and vaso-occlusive complications. Increasing evidence indicates that oxidative stress plays a central pathogenic role in SCD complications. Forkhead box O3 (FOXO3) is a key transcription factor involved in different cellular mechanisms, including apoptosis, autophagy, and cytoprotective signaling cascades. FOXO3, through its transcriptional modulation of enzymes such as superoxide dismutase, glutathione peroxidase, and catalase, reduces reactive oxygen species burden, delays hemolysis, and contributes to RBC longevity. Beyond its antioxidant defense properties, FOXO3 interacts with other key molecular pathways, such as nuclear factor erythroid 2-related factor 2, nuclear factor kappa B, AMP-activated protein kinase, and sirtuin 1, which modulate vascular inflammation, nitric oxide bioavailability, and systemic redox homeostasis. Thus, by promoting antioxidant defense and facilitating autophagy, FOXO3 emerges as both a biomarker and a promising therapeutic target in SCD. This review provides key findings from the existing literature and precisely explores FOXO3's role in cellular stress responses, antioxidant defense, fetal hemoglobin production, erythropoiesis, and RBC longevity, as well as their implications for disease severity and therapeutic strategies in SCD. Future studies focusing on patient-specific FOXO3 activity by precision modulation and multi-omics sequencing will be essential to fully harness FOXO3's potential to achieve beneficial outcomes for individuals with SCD.
{"title":"Role of FOXO3 in regulation of redox homeostasis and promotion of red blood cell longevity in sickle cell disease.","authors":"Eluri Pavitra, Meenoo Kumbhakar, Byeongsu Kim, Vivek Kumar Gupta, Pragati Gupta, Jeong-Hwan Lee, Young-Kyu Han, Lvks Bhaskar, Ganji Seeta Rama Raju, Yun Suk Huh","doi":"10.1016/j.cytogfr.2026.04.003","DOIUrl":"https://doi.org/10.1016/j.cytogfr.2026.04.003","url":null,"abstract":"<p><p>Sickle cell disease (SCD) is a severe monogenic red blood cell (RBC) disorder that follows a simple Mendelian mode of inheritance. SCD is characterized by hemoglobin S polymerization under deoxygenated conditions, leading to chronic hemolysis and vaso-occlusive complications. Increasing evidence indicates that oxidative stress plays a central pathogenic role in SCD complications. Forkhead box O3 (FOXO3) is a key transcription factor involved in different cellular mechanisms, including apoptosis, autophagy, and cytoprotective signaling cascades. FOXO3, through its transcriptional modulation of enzymes such as superoxide dismutase, glutathione peroxidase, and catalase, reduces reactive oxygen species burden, delays hemolysis, and contributes to RBC longevity. Beyond its antioxidant defense properties, FOXO3 interacts with other key molecular pathways, such as nuclear factor erythroid 2-related factor 2, nuclear factor kappa B, AMP-activated protein kinase, and sirtuin 1, which modulate vascular inflammation, nitric oxide bioavailability, and systemic redox homeostasis. Thus, by promoting antioxidant defense and facilitating autophagy, FOXO3 emerges as both a biomarker and a promising therapeutic target in SCD. This review provides key findings from the existing literature and precisely explores FOXO3's role in cellular stress responses, antioxidant defense, fetal hemoglobin production, erythropoiesis, and RBC longevity, as well as their implications for disease severity and therapeutic strategies in SCD. Future studies focusing on patient-specific FOXO3 activity by precision modulation and multi-omics sequencing will be essential to fully harness FOXO3's potential to achieve beneficial outcomes for individuals with SCD.</p>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"90 ","pages":"1-11"},"PeriodicalIF":11.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834916","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 : 2026-04-01Epub Date: 2026-02-04DOI: 10.1016/j.cytogfr.2026.01.008
Keda Chen , Qiuyi Xu , Jiaxuan Li , Guangshang Wu , Hao Wu , Xiaotian Tie , Jinghan Xu , Jianhua Li , Yanjun Zhang
Cytokine storm (CS) is a pathological state of dysregulated, hyperactive host immunity that arises in the context of infection, malignancy, or immunotherapy. CS is characterized by the sustained, markedly elevated release of multiple pro-inflammatory mediators, ultimately leading to tissue damage and multi-organ dysfunction. Upper respiratory viral infections, including SARS, MERS, SARS-CoV-2, influenza, adenovirus, and respiratory syncytial virus (RSV), are among the most prominent CS triggers. Inflammatory storms triggered by different pathogens exhibit distinct variations in their cytokine profiles and downstream immune signaling pathways. Underlying comorbidities—such as diabetes, obesity, and cardiovascular disease—together with complications such as coagulopathies and secondary infections, can profoundly alter both the threshold and the magnitude of the cytokine storm. This review systematically compares cytokine profiles elicited by distinct upper respiratory pathogens, with population stratification by age and underlying comorbidities, to clarify how these patterns relate to disease severity and complication risk. Collectively, the available evidence supports a shared inflammatory backbone across respiratory virus–induced cytokine storms, overlaid by pathogen-specific cytokine fingerprints and host-dependent plasticity that shapes clinical trajectories and outcomes.
{"title":"Cytokine storm divergence in viral infections of the upper respiratory tract","authors":"Keda Chen , Qiuyi Xu , Jiaxuan Li , Guangshang Wu , Hao Wu , Xiaotian Tie , Jinghan Xu , Jianhua Li , Yanjun Zhang","doi":"10.1016/j.cytogfr.2026.01.008","DOIUrl":"10.1016/j.cytogfr.2026.01.008","url":null,"abstract":"<div><div>Cytokine storm (CS) is a pathological state of dysregulated, hyperactive host immunity that arises in the context of infection, malignancy, or immunotherapy. CS is characterized by the sustained, markedly elevated release of multiple pro-inflammatory mediators, ultimately leading to tissue damage and multi-organ dysfunction. Upper respiratory viral infections, including SARS, MERS, SARS-CoV-2, influenza, adenovirus, and respiratory syncytial virus (RSV), are among the most prominent CS triggers. Inflammatory storms triggered by different pathogens exhibit distinct variations in their cytokine profiles and downstream immune signaling pathways. Underlying comorbidities—such as diabetes, obesity, and cardiovascular disease—together with complications such as coagulopathies and secondary infections, can profoundly alter both the threshold and the magnitude of the cytokine storm. This review systematically compares cytokine profiles elicited by distinct upper respiratory pathogens, with population stratification by age and underlying comorbidities, to clarify how these patterns relate to disease severity and complication risk. Collectively, the available evidence supports a shared inflammatory backbone across respiratory virus–induced cytokine storms, overlaid by pathogen-specific cytokine fingerprints and host-dependent plasticity that shapes clinical trajectories and outcomes.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"88 ","pages":"Pages 108-123"},"PeriodicalIF":11.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141334","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 : 2026-04-01Epub Date: 2026-01-16DOI: 10.1016/j.cytogfr.2026.01.005
Mai P. Ho , Megan Jung , William Ung , Evagelia Skouradaki , Stavroula Baritaki , Benjamin Bonavida
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by a dense desmoplastic stroma, profound immune suppression, and resistance to conventional therapeutics. Poor patient outcomes are driven by resistance to chemotherapy and immunotherapy arising from both tumor-intrinsic and microenvironmental mechanisms. Elucidating the molecular pathways underlying therapeutic failure is therefore critical. Transforming growth factor-β (TGF-β) is a central regulator of PDAC progression, promoting epithelial–mesenchymal-transition (EMT), stromal remodeling, immune exclusion, and checkpoint activation at advanced disease stages. The transcription factor Yin Yang 1 (YY1) is a critical downstream integrator and amplifier of TGF-β–driven signaling programs. YY1 reinforces EMT, metabolic adaptation, and immune evasion through transcriptional, epigenetic, and post-transcriptional regulations. Several key immune modulators of immune evasion include PD-L1, indoleamine 2,3-dioxygenase, FOXP3, and pro-tumoral chemokines. The coordinated TGF-β–YY1 signaling suppresses CD8 cytotoxic T-cell (CTL) and natural killer (NK) cell functions, promotes regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), and establishes an immune-cold, therapy-resistant tumor microenvironment. This review explores the mechanistic basis of the TGF-β-YY1 cross-talk regulation in the immune evasion of PDAC. It also discusses emerging therapeutic opportunities in targeting the TGF-β-YY1 axis to overcome immune escape and improve treatment outcomes in PDAC.
{"title":"TGF-β–YY1 signaling as a key driver of immune evasion in pancreatic cancer: Therapeutic implications","authors":"Mai P. Ho , Megan Jung , William Ung , Evagelia Skouradaki , Stavroula Baritaki , Benjamin Bonavida","doi":"10.1016/j.cytogfr.2026.01.005","DOIUrl":"10.1016/j.cytogfr.2026.01.005","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by a dense desmoplastic stroma, profound immune suppression, and resistance to conventional therapeutics. Poor patient outcomes are driven by resistance to chemotherapy and immunotherapy arising from both tumor-intrinsic and microenvironmental mechanisms. Elucidating the molecular pathways underlying therapeutic failure is therefore critical. Transforming growth factor-β (TGF-β) is a central regulator of PDAC progression, promoting epithelial–mesenchymal-transition (EMT), stromal remodeling, immune exclusion, and checkpoint activation at advanced disease stages. The transcription factor Yin Yang 1 (YY1) is a critical downstream integrator and amplifier of TGF-β–driven signaling programs. YY1 reinforces EMT, metabolic adaptation, and immune evasion through transcriptional, epigenetic, and post-transcriptional regulations. Several key immune modulators of immune evasion include PD-L1, indoleamine 2,3-dioxygenase, FOXP3, and pro-tumoral chemokines. The coordinated TGF-β–YY1 signaling suppresses CD8 cytotoxic T-cell (CTL) and natural killer (NK) cell functions, promotes regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), and establishes an immune-cold, therapy-resistant tumor microenvironment. This review explores the mechanistic basis of the TGF-β-YY1 cross-talk regulation in the immune evasion of PDAC. It also discusses emerging therapeutic opportunities in targeting the TGF-β-YY1 axis to overcome immune escape and improve treatment outcomes in PDAC.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"88 ","pages":"Pages 58-66"},"PeriodicalIF":11.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146009276","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 : 2026-04-01Epub Date: 2026-01-13DOI: 10.1016/j.cytogfr.2026.01.004
Lingeng Lu , Caroline H. Johnson , Sajid A. Khan , Melinda L. Irwin
Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGFβ) superfamily, has emerged as a pivotal cytokine linking cancer metabolism, immune suppression, and systemic energy balance. Initially characterized as a stress-induced cytokine with roles in appetite regulation and cachexia, GDF15 was first identified in activated macrophages and is also secreted by tumor cells, stromal cells and stressed epithelial cells across multiple tissues. Functionally, GDF15 exerts pleiotropic effects on both immune and nonimmune cell populations, modulating T cells, dendritic cells, and macrophages in the tumor microenvironment (TME), and metabolic tissues such as liver, adipose and muscle, thereby promoting tumor progression, therapeutic resistance, and cancer-associated metabolic dysregulation. In several human cancers of such as colorectal, pancreatic, breast and brain, elevated GDF15 levels correlate with poor prognosis, immune evasion, and chemoresistance. Mechanistically, GDF15 modulates fatty acid metabolism, promotes epithelial-mesenchymal transition, and suppresses anti-tumor immunity by impairing dendritic cell maturation and excluding CD8+ T cell infiltration. Targeting GDF15 may reprogram immunometabolic suppression and enhance checkpoint blockade efficacy. This review synthesizes current knowledge on GDF15’s multifaceted roles in tumor biology, emphasizing its function as a central node of cancer immunometabolism. We highlight advances in spatial multi-omics, integrating transcriptomics and immune imaging, that reveal GDF15 spatially restricted immunosuppression in the tumor microenvironment.
{"title":"GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance","authors":"Lingeng Lu , Caroline H. Johnson , Sajid A. Khan , Melinda L. Irwin","doi":"10.1016/j.cytogfr.2026.01.004","DOIUrl":"10.1016/j.cytogfr.2026.01.004","url":null,"abstract":"<div><div>Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGFβ) superfamily, has emerged as a pivotal cytokine linking cancer metabolism, immune suppression, and systemic energy balance. Initially characterized as a stress-induced cytokine with roles in appetite regulation and cachexia, GDF15 was first identified in activated macrophages and is also secreted by tumor cells, stromal cells and stressed epithelial cells across multiple tissues. Functionally, GDF15 exerts pleiotropic effects on both immune and nonimmune cell populations, modulating T cells, dendritic cells, and macrophages in the tumor microenvironment (TME), and metabolic tissues such as liver, adipose and muscle, thereby promoting tumor progression, therapeutic resistance, and cancer-associated metabolic dysregulation. In several human cancers of such as colorectal, pancreatic, breast and brain, elevated GDF15 levels correlate with poor prognosis, immune evasion, and chemoresistance. Mechanistically, GDF15 modulates fatty acid metabolism, promotes epithelial-mesenchymal transition, and suppresses anti-tumor immunity by impairing dendritic cell maturation and excluding CD8<sup>+</sup> T cell infiltration. Targeting GDF15 may reprogram immunometabolic suppression and enhance checkpoint blockade efficacy. This review synthesizes current knowledge on GDF15’s multifaceted roles in tumor biology, emphasizing its function as a central node of cancer immunometabolism. We highlight advances in spatial multi-omics, integrating transcriptomics and immune imaging, that reveal GDF15 spatially restricted immunosuppression in the tumor microenvironment.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"88 ","pages":"Pages 47-57"},"PeriodicalIF":11.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975138","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}
Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which neuroinflammation plays a key role. An imbalance between pro- and anti-inflammatory cytokines has been observed in both experimental models and PD patients. The inflammatory mediators activate signaling pathways that lead to oxidative stress, excitotoxicity, blood-brain barrier (BBB) disruption, gut dysbiosis, and hypothalamic–pituitary–adrenal axis (HPA-axis) dysregulation. Increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and others, following PD, stimulate both glial and peripheral immune cells to migrate to injury sites, further promoting neuroinflammation. Cytokines can directly cause neuronal damage and death through various mechanisms. These pathological changes eventually contribute to α-synuclein aggregation and the loss of dopaminergic neurons. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which promotes IL-1β maturation and caspase-1-driven neurotoxicity, has become a critical molecular hub linking innate immune activation to disease progression. Preclinical and clinical studies support that drugs targeting cytokine signaling can reduce neurotoxicity and neurodegeneration. Therapeutic agents that modulate pathways such as ephrin, cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING), Hippo, Receptor-Interacting Protein Kinase 1 (RIPK1), Leucine-rich repeat kinase 2 (LRRK2), and sirtuin pathways have shown anti-inflammatory effects in PD models. Combining approaches targeting immune and cytokine pathways offers a promising strategy for neuroprotection and disease modification in PD.
{"title":"Cytokine associated neuroinflammation in Parkinson’s disease: Molecular pathways, therapeutic targets, and translational insights","authors":"Rishika Dhapola , Sneha Kumari , Prajjwal Sharma , Mohit Paidlewar , Balachandar Vellingiri , Bikash Medhi , Dibbanti HariKrishnaReddy","doi":"10.1016/j.cytogfr.2026.01.001","DOIUrl":"10.1016/j.cytogfr.2026.01.001","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which neuroinflammation plays a key role. An imbalance between pro- and anti-inflammatory cytokines has been observed in both experimental models and PD patients. The inflammatory mediators activate signaling pathways that lead to oxidative stress, excitotoxicity, blood-brain barrier (BBB) disruption, gut dysbiosis, and hypothalamic–pituitary–adrenal axis (HPA-axis) dysregulation. Increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and others, following PD, stimulate both glial and peripheral immune cells to migrate to injury sites, further promoting neuroinflammation. Cytokines can directly cause neuronal damage and death through various mechanisms. These pathological changes eventually contribute to α-synuclein aggregation and the loss of dopaminergic neurons. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which promotes IL-1β maturation and caspase-1-driven neurotoxicity, has become a critical molecular hub linking innate immune activation to disease progression. Preclinical and clinical studies support that drugs targeting cytokine signaling can reduce neurotoxicity and neurodegeneration. Therapeutic agents that modulate pathways such as ephrin, cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING), Hippo, Receptor-Interacting Protein Kinase 1 (RIPK1), Leucine-rich repeat kinase 2 (LRRK2), and sirtuin pathways have shown anti-inflammatory effects in PD models. Combining approaches targeting immune and cytokine pathways offers a promising strategy for neuroprotection and disease modification in PD.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"88 ","pages":"Pages 1-17"},"PeriodicalIF":11.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145915492","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}
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a poor prognosis due to its complex and highly immunosuppressive tumor microenvironment (TME). The PDAC TME, characterized by dense desmoplasia and enhanced infiltration of immunosuppressive immune cells, acts as a physical and immunological barrier, rendering most patients unresponsive to conventional and immune checkpoint inhibitor (ICI) therapies. This resistance is critically mediated by the cytokine network, where pro-tumorigenic factors such as IL-6 and TGF-β drive T-cell exclusion and myeloid-dependent suppression from PSCs, CAFs, and immune cells. The key to improving the therapeutic approaches lies in effectively reprogramming this hostile milieu. This review focuses on the dual and paradoxical role of cytokines as drivers of immune evasion (IL-6, TGF-β, MIF) and mediators of anti-tumor immunity (IL-12, IL-15). Herein, we outline the strategic shift toward cytokine-based combination immunotherapy designed to remodel the TME through the disruption of cytokine-driven resistance pathways. Key strategies currently under investigation include targeting TGF-β and IL-6 to sensitize tumors to ICIs, while antagonizing chemokines like CXCL12/CXCR4 to enhance T-cell trafficking. Furthermore, we detailed cutting-edge approaches to overcome systemic toxicity and poor drug delivery, specifically through cytokine-based nanotechnology, including nanocarriers and mRNA lipid nanoparticles, for localized expression of immunogenic signals. As well as the cutting-edge field of chimeric cytokine engineering, including VHH-fusions, to selectively activate anti-tumor immunity, highlighting promising candidates in late-stage clinical trials. The successful application of these engineered cytokine strategies is crucial to unlocking effective immunotherapy for PDAC patients.
{"title":"Cytokine circuitry in pancreatic cancer: Targets for overcoming immune checkpoint inhibitor resistance in PDAC","authors":"Dhanisha Sulekha Suresh , Maria Fernanda Salcedo-Noriega , Utpreksha Vaish , Abhiram Beena Kannan , Suryansh Suryansh , Sweta Bhandari , Saikiran Chatre , Tejeshwar Jain , Vivaan Dudeja , Srikanth Iyer","doi":"10.1016/j.cytogfr.2026.01.009","DOIUrl":"10.1016/j.cytogfr.2026.01.009","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a poor prognosis due to its complex and highly immunosuppressive tumor microenvironment (TME). The PDAC TME, characterized by dense desmoplasia and enhanced infiltration of immunosuppressive immune cells, acts as a physical and immunological barrier, rendering most patients unresponsive to conventional and immune checkpoint inhibitor (ICI) therapies. This resistance is critically mediated by the cytokine network, where pro-tumorigenic factors such as IL-6 and TGF-β drive T-cell exclusion and myeloid-dependent suppression from PSCs, CAFs, and immune cells. The key to improving the therapeutic approaches lies in effectively reprogramming this hostile milieu. This review focuses on the dual and paradoxical role of cytokines as drivers of immune evasion (IL-6, TGF-β, MIF) and mediators of anti-tumor immunity (IL-12, IL-15). Herein, we outline the strategic shift toward cytokine-based combination immunotherapy designed to remodel the TME through the disruption of cytokine-driven resistance pathways. Key strategies currently under investigation include targeting TGF-β and IL-6 to sensitize tumors to ICIs, while antagonizing chemokines like CXCL12/CXCR4 to enhance T-cell trafficking. Furthermore, we detailed cutting-edge approaches to overcome systemic toxicity and poor drug delivery, specifically through cytokine-based nanotechnology, including nanocarriers and mRNA lipid nanoparticles, for localized expression of immunogenic signals. As well as the cutting-edge field of chimeric cytokine engineering, including VHH-fusions, to selectively activate anti-tumor immunity, highlighting promising candidates in late-stage clinical trials. The successful application of these engineered cytokine strategies is crucial to unlocking effective immunotherapy for PDAC patients.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"88 ","pages":"Pages 124-137"},"PeriodicalIF":11.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156124","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 : 2026-04-01Epub Date: 2026-01-09DOI: 10.1016/j.cytogfr.2026.01.003
Jinsun Jang , Minji Park , Hee Joo Kim , YunJae Jung
Obesity and psoriasis are chronic inflammatory disorders, now recognized to be interconnected, in which metabolic overload drives immune dysregulation and therapeutic resistance. Excess adiposity converts adipose tissue into an inflammatory organ that releases adipokines and cytokine-like mediators, reprogramming keratinocytes and immune cells to sustain cytokine-driven inflammatory circuits in the skin. Excess nutrients and lipotoxic stress impair mitochondrial function, enhance glycolysis, and induce epigenetic remodeling in myeloid and epithelial lineages, generating metabolic memory that perpetuates inflammation. Increased body mass index and insulin resistance are clinically associated with reduced responses to biologics targeting tumor necrosis factor, interleukin (IL)-17, and IL-23, whereas metabolic interventions including caloric restriction and glucagon-like peptide-1 receptor agonists improve responsiveness. Recent multi-omics, single-cell, and spatial studies demonstrate that obesity reshapes dermal and adipose immune niches and rewires epidermal innate immunity, attenuating cytokine blockade. Obesity-associated psoriasis thus represents a metabolically imprinted inflammatory state driven by chronic metabolic stress. This review integrates mechanistic and clinical insights and discusses strategies to restore metabolic–immune plasticity to sustain disease remission.
{"title":"Reprogramming immunity at the metabolic–epidermal interface in obesity-associated psoriasis","authors":"Jinsun Jang , Minji Park , Hee Joo Kim , YunJae Jung","doi":"10.1016/j.cytogfr.2026.01.003","DOIUrl":"10.1016/j.cytogfr.2026.01.003","url":null,"abstract":"<div><div>Obesity and psoriasis are chronic inflammatory disorders, now recognized to be interconnected, in which metabolic overload drives immune dysregulation and therapeutic resistance. Excess adiposity converts adipose tissue into an inflammatory organ that releases adipokines and cytokine-like mediators, reprogramming keratinocytes and immune cells to sustain cytokine-driven inflammatory circuits in the skin. Excess nutrients and lipotoxic stress impair mitochondrial function, enhance glycolysis, and induce epigenetic remodeling in myeloid and epithelial lineages, generating metabolic memory that perpetuates inflammation. Increased body mass index and insulin resistance are clinically associated with reduced responses to biologics targeting tumor necrosis factor, interleukin (IL)-17, and IL-23, whereas metabolic interventions including caloric restriction and glucagon-like peptide-1 receptor agonists improve responsiveness. Recent multi-omics, single-cell, and spatial studies demonstrate that obesity reshapes dermal and adipose immune niches and rewires epidermal innate immunity, attenuating cytokine blockade. Obesity-associated psoriasis thus represents a metabolically imprinted inflammatory state driven by chronic metabolic stress. This review integrates mechanistic and clinical insights and discusses strategies to restore metabolic–immune plasticity to sustain disease remission.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"88 ","pages":"Pages 32-46"},"PeriodicalIF":11.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975137","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 : 2026-04-01Epub Date: 2026-02-17DOI: 10.1016/j.cytogfr.2026.02.002
Shannah M. Gennesse , Rory R. Koenen , Victor L.J.L. Thijssen
The human immune system is a complex defense mechanism that protects the body against external and internal threats. Disruption of an effective immune response can lead to detrimental effects, such as autoimmune diseases or cancer. To ensure an adequate response, a complex network of immunoregulatory pathways exists. Cytokines and galectins represent two immunoregulatory protein families that, for long, were considered to act independently. Current research shows that the expression and secretion of galectins and cytokines is reciprocally controlled. More recently, cytokines and galectins were found to form heterodimers, affecting protein functionality. All these findings suggest a cooperative activity of cytokines and galectins during immune regulation. To fully understand their combined immunoregulatory capacities, it is essential to investigate this reciprocal relationship between cytokines and galectins. Here, we summarize our current knowledge regarding the regulatory and functional relationship between galectins and cytokines in the context of the immune response.
{"title":"The intricate relationship between cytokines and galectins in immune modulation","authors":"Shannah M. Gennesse , Rory R. Koenen , Victor L.J.L. Thijssen","doi":"10.1016/j.cytogfr.2026.02.002","DOIUrl":"10.1016/j.cytogfr.2026.02.002","url":null,"abstract":"<div><div>The human immune system is a complex defense mechanism that protects the body against external and internal threats. Disruption of an effective immune response can lead to detrimental effects, such as autoimmune diseases or cancer. To ensure an adequate response, a complex network of immunoregulatory pathways exists. Cytokines and galectins represent two immunoregulatory protein families that, for long, were considered to act independently. Current research shows that the expression and secretion of galectins and cytokines is reciprocally controlled. More recently, cytokines and galectins were found to form heterodimers, affecting protein functionality. All these findings suggest a cooperative activity of cytokines and galectins during immune regulation. To fully understand their combined immunoregulatory capacities, it is essential to investigate this reciprocal relationship between cytokines and galectins. Here, we summarize our current knowledge regarding the regulatory and functional relationship between galectins and cytokines in the context of the immune response.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"88 ","pages":"Pages 152-166"},"PeriodicalIF":11.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146775916","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 : 2026-04-01Epub Date: 2025-12-13DOI: 10.1016/j.cytogfr.2025.12.007
Wenxue Ma, Jessica Pham, Catriona Jamieson
T cells have traditionally been characterized as autonomous killers that eliminate malignant cells through single-cell cytotoxicity. However, recent findings reveal that tumor-reactive T cells frequently form tightly bound clusters on the tumor surface, functioning as cooperative hyper-effector units. These clusters establish stable and reinforced immune synapses, sustain prolonged engagement with tumor targets, and coordinate the delivery of perforin, granzymes, and proinflammatory cytokines. As a result, they exhibit markedly enhanced tumor-killing capacity compared with unbound T cells in both ex vivo assays and murine models. This discovery introduces an essential spatial and mechanical dimension to cancer immunology and challenges the prevailing assumption that molecular phenotype alone defines T-cell efficacy. The implications are substantial, extending to tumor-infiltrating lymphocyte (TIL) therapy optimization, the refinement of immunotherapy biomarkers, and the engineering of next-generation CAR-T and CAR-NK platforms. Enriching or mimicking the behavior of cluster-forming T cells may accelerate clinical responses and overcome barriers associated with solid tumors. Collectively, these insights reposition T-cell clustering as a fundamental determinant of effective antitumor immunity.
{"title":"Tightly bound T-cell clusters: A new class of hyper-effector tumor killers","authors":"Wenxue Ma, Jessica Pham, Catriona Jamieson","doi":"10.1016/j.cytogfr.2025.12.007","DOIUrl":"10.1016/j.cytogfr.2025.12.007","url":null,"abstract":"<div><div>T cells have traditionally been characterized as autonomous killers that eliminate malignant cells through single-cell cytotoxicity. However, recent findings reveal that tumor-reactive T cells frequently form tightly bound clusters on the tumor surface, functioning as cooperative hyper-effector units. These clusters establish stable and reinforced immune synapses, sustain prolonged engagement with tumor targets, and coordinate the delivery of perforin, granzymes, and proinflammatory cytokines. As a result, they exhibit markedly enhanced tumor-killing capacity compared with unbound T cells in both ex vivo assays and murine models. This discovery introduces an essential spatial and mechanical dimension to cancer immunology and challenges the prevailing assumption that molecular phenotype alone defines T-cell efficacy. The implications are substantial, extending to tumor-infiltrating lymphocyte (TIL) therapy optimization, the refinement of immunotherapy biomarkers, and the engineering of next-generation CAR-T and CAR-NK platforms. Enriching or mimicking the behavior of cluster-forming T cells may accelerate clinical responses and overcome barriers associated with solid tumors. Collectively, these insights reposition T-cell clustering as a fundamental determinant of effective antitumor immunity.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"88 ","pages":"Pages 105-107"},"PeriodicalIF":11.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800307","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 : 2026-04-01Epub Date: 2026-01-06DOI: 10.1016/j.cytogfr.2026.01.002
Chaopeng He , Guiwu Huang , Jingwei Bi, Wenyu Fu, Chuan-ju Liu
Cytosolic phospholipase A2 (cPLA2) is a central regulator of lipid signaling that links cytokine and growth factor signaling to arachidonic acid metabolism and downstream eicosanoid production. Dysregulated cPLA2 activity is increasingly recognized as a shared pathogenic mechanism across musculoskeletal and autoimmune diseases, including osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, osteoporosis, inflammatory myopathies, sarcopenia and Duchenne muscular dystrophy, as well as inflammatory bowel disease and multiple sclerosis. This review provides a focused and mechanistic overview of cPLA2 biology, emphasizing its regulation by Ca²⁺-dependent membrane translocation and MAPK-mediated phosphorylation, and its cell type specific actions in chondrocytes, osteoblasts, osteoclasts, myocytes, and immune cells. We discuss how cPLA2-driven lipid mediators coordinate inflammation, extracellular-matrix turnover, mitochondrial dysfunction, cellular senescence, and immune cell activation to drive chronic tissue degeneration. Importantly, we summarize emerging therapeutic strategies targeting cPLA2, spanning selective small-molecule inhibitors, gene-editing approaches, and drug repurposing (e.g., pyruvate and fexofenadine), and discuss their translational promise. Collectively, these insights position cPLA2 as a master regulator linking lipid metabolism with inflammation and tissue remodeling and may provide a unifying framework for developing disease-modifying therapies across diverse inflammatory and degenerative conditions, particularly musculoskeletal and autoimmune disorders.
{"title":"cPLA2 in musculoskeletal and autoimmune diseases: Molecular mechanisms and therapeutic insights","authors":"Chaopeng He , Guiwu Huang , Jingwei Bi, Wenyu Fu, Chuan-ju Liu","doi":"10.1016/j.cytogfr.2026.01.002","DOIUrl":"10.1016/j.cytogfr.2026.01.002","url":null,"abstract":"<div><div>Cytosolic phospholipase A2 (cPLA2) is a central regulator of lipid signaling that links cytokine and growth factor signaling to arachidonic acid metabolism and downstream eicosanoid production. Dysregulated cPLA2 activity is increasingly recognized as a shared pathogenic mechanism across musculoskeletal and autoimmune diseases, including osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, osteoporosis, inflammatory myopathies, sarcopenia and Duchenne muscular dystrophy, as well as inflammatory bowel disease and multiple sclerosis. This review provides a focused and mechanistic overview of cPLA2 biology, emphasizing its regulation by Ca²⁺-dependent membrane translocation and MAPK-mediated phosphorylation, and its cell type specific actions in chondrocytes, osteoblasts, osteoclasts, myocytes, and immune cells. We discuss how cPLA2-driven lipid mediators coordinate inflammation, extracellular-matrix turnover, mitochondrial dysfunction, cellular senescence, and immune cell activation to drive chronic tissue degeneration. Importantly, we summarize emerging therapeutic strategies targeting cPLA2, spanning selective small-molecule inhibitors, gene-editing approaches, and drug repurposing (e.g., pyruvate and fexofenadine), and discuss their translational promise. Collectively, these insights position cPLA2 as a master regulator linking lipid metabolism with inflammation and tissue remodeling and may provide a unifying framework for developing disease-modifying therapies across diverse inflammatory and degenerative conditions, particularly musculoskeletal and autoimmune disorders.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"88 ","pages":"Pages 18-31"},"PeriodicalIF":11.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145915493","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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