The interaction between the tumor immune microenvironment (TIME) and the tumor determines whether immune evasion or antitumor immunity prevails. Metabolic reprogramming is increasingly recognized as a critical factor sha...The interaction between the tumor immune microenvironment (TIME) and the tumor determines whether immune evasion or antitumor immunity prevails. Metabolic reprogramming is increasingly recognized as a critical factor shaping the tumor immune response. Glucose metabolism regulates the intrinsic cellular states of both immune and tumor cells, while simultaneously shaping the surrounding microenvironment. The glycolytic diversity of immune and tumor cells drives the complexity of the TIME. In this Review, we explore how glucose metabolism remodels the TIME and how these metabolic alterations influence immune effector function and immune evasion. We also highlight the potential for integrating microenvironmental modulation as a promising therapeutic strategy in glucose-targeted cancer therapies.
Gunn JL, Rubina A, Fielding CA
… +4 more, Mohammed F, Wang ECY, Willcox CR, Willcox BE
Trends Immunol
· 2026 Feb · PMID 41330829
·
Full text
Identification of antigenic ligands for the γδ T cell receptor (TCR) has remained a highly challenging goal since the emergence in the 1980s of γδ T cells as a distinct immune compartment. In a significant advance more t...Identification of antigenic ligands for the γδ T cell receptor (TCR) has remained a highly challenging goal since the emergence in the 1980s of γδ T cells as a distinct immune compartment. In a significant advance more than 12 years ago, endothelial protein C receptor (EPCR), a cell-surface-expressed major histocompatibility complex (MHC)-like protein that binds phospholipids, was identified as the first ligand for a human γδ TCR to be validated by direct binding experiments: a finding that undoubtedly posed more questions than it answered. In this review we discuss how features of this single clonotypic specificity anticipated insights into adaptive-like human γδ T cell biology that emerged in subsequent investigations, and we highlight recent findings about EPCR that point towards the relevance of such responses in anti-pathogen and potentially anti-tumour immunity.
Programmed cell death (PCD) encompasses several tightly regulated molecular signalling pathways, leading to the controlled destruction of cells. Apoptosis is a non-immunogenic form of cell death that regulates homeostasi...Programmed cell death (PCD) encompasses several tightly regulated molecular signalling pathways, leading to the controlled destruction of cells. Apoptosis is a non-immunogenic form of cell death that regulates homeostasis to cell stressors. In contrast, lytic forms of cell death - necroptosis, pyroptosis, and ferroptosis - promote inflammation, alerting the immune system to danger. As adaptive immune responders, T cells clonally expand in response to antigenic stimulation and rapidly contract following the clearance of infection. While the role of apoptosis in regulating these processes is relatively well understood, evidence for lytic death activity in T cells is emerging. This review provides an update on recent advances in the understanding of PCD pathways in conventional and unconventional T cells in diverse immune contexts.
Trends Immunol
· 2026 Apr · PMID 41290494
·
Full text
The maintenance of serum antibodies requires the persistence of plasma cells within the bone marrow (BM). However, little is understood about why relatively few BM plasma cells live for extended periods. We consider two...The maintenance of serum antibodies requires the persistence of plasma cells within the bone marrow (BM). However, little is understood about why relatively few BM plasma cells live for extended periods. We consider two opposing viewpoints. We first consider the notion that sustained antibody titers requires localization of plasma cells to specialized BM niches where they access cell extrinsic survival factors, including extracellular ATP (eATP). We then consider the alternative possibility that plasma cell survival requires optimized cell intrinsic control of antibody synthesis supported by eATP stimulation of purinergic receptors. Based on the latter view we propose that many BM plasma cells fail to achieve maximal longevity due to suboptimal protein homeostasis rather than compromised access to cell extrinsic survival cues.
Inflammasomes have emerged as central regulators of (auto)immune pathology, including multiple sclerosis (MS). Once exclusively considered in the domain of myeloid cells, both canonical and noncanonical inflammasomes are...Inflammasomes have emerged as central regulators of (auto)immune pathology, including multiple sclerosis (MS). Once exclusively considered in the domain of myeloid cells, both canonical and noncanonical inflammasomes are now recognized in diverse immune and nonimmune populations relevant to MS, including T lymphocytes, blood-brain barrier (BBB) endothelial cells (EnC), and oligodendrocytes (ODCs). Elevated inflammasome activity is evident in patient-derived samples, particularly within active brain lesions. Experimental autoimmune encephalomyelitis (EAE) models confirm the pathogenic contribution of inflammasomes, as genetic deletion or pharmacological inhibition of inflammasomes mitigate disease. These advances position inflammasomes at the intersection of neuroinflammation and neurodegeneration, and highlight inflammasome inhibition as a promising therapeutic avenue currently under investigation in preclinical and early clinical studies.
IL-22, produced by various cell types including T helper (Th) 17 cells and group 3 innate lymphoid cells (ILC3s), plays a pivotal role in gut homeostasis by acting on non-hematopoietic cells. It promotes epithelial barri...IL-22, produced by various cell types including T helper (Th) 17 cells and group 3 innate lymphoid cells (ILC3s), plays a pivotal role in gut homeostasis by acting on non-hematopoietic cells. It promotes epithelial barrier integrity, tissue repair, and antimicrobial defense. Beyond its established function in mucosal immunity, emerging evidence reveals IL-22's involvement in regulating intestinal metabolism and protecting against systemic metabolic dysregulation. This review highlights recent advances in preclinical mouse models and human clinical data in IL-22 biology, focusing on its dual role in immune defense and metabolic control. Given the strong link between inflammatory bowel disease (IBD) and metabolic disorders, we further discuss IL-22's therapeutic potential in mitigating both intestinal inflammation and related metabolic complications.
Trends Immunol
· 2026 Apr · PMID 41266200
·
Full text
Interleukin-27 (IL-27), a member of the IL-12 cytokine family, was long viewed primarily as a regulator of CD4 T cell immunity. Subsequent studies revealed that IL-27 also directly modulates CD8 T cells, displaying both...Interleukin-27 (IL-27), a member of the IL-12 cytokine family, was long viewed primarily as a regulator of CD4 T cell immunity. Subsequent studies revealed that IL-27 also directly modulates CD8 T cells, displaying both stimulatory and inhibitory potential. Recent work extends this earlier literature, showing that IL-27 in infection and cancer can promote effector differentiation, sustain survival, and reverse dysfunction, often without the systemic toxicity associated with related cytokines. This review outlines the molecular features, signaling mechanisms, and cellular sources of IL-27, integrating emerging evidence from viral, tumor, and autoimmune settings. We propose that IL-27 operates not as an inherently pro- or anti-inflammatory cytokine but as a context-dependent tuner of CD8 T cell cytotoxic immunity, offering new opportunities for therapeutic exploitation.
Chi and colleagues revealed that dietary cysteine enhances intestinal stem cell (ISC) regeneration, driving coenzyme A (CoA) synthesis and expansion of intraepithelial (IEL) CD8αβ T cells that secrete IL-22. This epithel...Chi and colleagues revealed that dietary cysteine enhances intestinal stem cell (ISC) regeneration, driving coenzyme A (CoA) synthesis and expansion of intraepithelial (IEL) CD8αβ T cells that secrete IL-22. This epithelial-immune crosstalk potentiates ISC repair after injury, highlighting a metabolism-immune axis linking cysteine sensing to tissue regeneration.
Burn et al. reveal a previously unrecognised, non-catalytic function of myeloperoxidase (MPO) in neutrophil extracellular trap (NET) formation; integrating super-resolution microscopy and biochemical approaches, they dem...Burn et al. reveal a previously unrecognised, non-catalytic function of myeloperoxidase (MPO) in neutrophil extracellular trap (NET) formation; integrating super-resolution microscopy and biochemical approaches, they demonstrated that MPO's oligomeric state governs chromatin decondensation, redefining MPO as a structural chromatin modifier with implications for diseases driven by dysregulated NETosis.
Trends Immunol
· 2026 Mar · PMID 41238442
·
Full text
Recent research has shown that sequential colonization of the skin by various subsets of immune cells, particularly T cells, during perinatal stages forms layered surveillance networks crucial for maintaining skin tissue...Recent research has shown that sequential colonization of the skin by various subsets of immune cells, particularly T cells, during perinatal stages forms layered surveillance networks crucial for maintaining skin tissue integrity and function. Here, we review our current understanding of key epigenetic and molecular mechanisms, along with maternal/external environmental factors, that regulate the sequential colonization of skin by different T cell subsets and their roles in establishing and maintaining skin tissue homeostasis. We propose that establishment of a skin-resident T cell system is developmentally programmed in coordination with maturation of skin structural barriers to adapt to environmental changes during perinatal stages, while dysregulation during this critical 'window of opportunity' could have lifelong impacts on the health of both the skin and body.
Trends Immunol
· 2026 Feb · PMID 41219086
·
Full text
The NLRP3 inflammasome plays a central role in host defense against microbial infections but also contributes to inflammatory diseases. Functioning of NLRP3 strictly relies on two signals: a 'priming signal' that license...The NLRP3 inflammasome plays a central role in host defense against microbial infections but also contributes to inflammatory diseases. Functioning of NLRP3 strictly relies on two signals: a 'priming signal' that licenses NLRP3 activity and an 'activation signal' that triggers inflammasome assembly and downstream caspase-1 activation. The priming signal involves transcriptional upregulation of NLRP3 and diverse post-translational modifications that regulate its stability, subcellular localization, and protein-protein interactions. This multilayered regulation prevents untimely inflammasome activation while enabling its rapid assembly when both priming and activation signals are present. Here, we focus on the complexity of the priming signal and critically analyze and discuss how diverse post-translational modifications cooperate to prime NLRP3, controlling its activity in health and disease.
HIV-1 persists lifelong despite effective antiretroviral therapy, yet the mechanisms underlying this persistence remain incompletely understood. Recent work by Wei et al. and Gao et al. reveals that the transcription fac...HIV-1 persists lifelong despite effective antiretroviral therapy, yet the mechanisms underlying this persistence remain incompletely understood. Recent work by Wei et al. and Gao et al. reveals that the transcription factor BACH2 orchestrates CD4 T cell memory programs fostering long-term memory formation while limiting effector differentiation, thereby promoting HIV-1 persistence.
Germinal center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) originates from the malignant transformation of germinal center B cells. This process is driven by transcriptional and epigenetic dysregulations, freq...Germinal center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) originates from the malignant transformation of germinal center B cells. This process is driven by transcriptional and epigenetic dysregulations, frequently caused by recurrent mutations and chromosomal translocations. These changes lead to a differentiation arrest associated with unchecked proliferation and survival. This review highlights key transcriptional and epigenetic dependencies that sustain the GCB-DLBCL phenotype and identifies therapeutic vulnerabilities. Epigenetic targeting of these vulnerabilities unlocks tumor cells from their differentiation arrest, enabling further yet incomplete differentiation toward an antiproliferative, proapoptotic plasma cell-like or memory B cell-like state. We define this transition as an epigenetically programmed identity crisis, a promising therapeutic strategy to target GCB-DLBCL and potentially other malignancies.
Trained immunity (TRIM) is a de facto form of innate immune memory. While histone modifications contribute to TRIM, their reversible nature and susceptibility to dilution during cell division cannot fully account for its...Trained immunity (TRIM) is a de facto form of innate immune memory. While histone modifications contribute to TRIM, their reversible nature and susceptibility to dilution during cell division cannot fully account for its long-term persistence. Here, we propose that DNA methylation patterns, particularly hypomethylation at proinflammatory gene loci, could serve as a key epigenetic mechanism contributing to long-term TRIM. Mechanistically, these hypomethylated states are biochemically stable and faithfully inherited through cell division, acting as a permissive scaffold that enables the rapid accumulation of activating histone marks upon restimulation. This DNA-methylation-mediated process could underpin the durability of TRIM across multiple contexts, including hematopoietic stem cell self-renewal, differentiation from central to peripheral compartments, and autonomy of tissue-resident cells.
Orthoflaviviruses - including dengue, Zika, yellow fever, Japanese encephalitis, and Powassan viruses - are mosquito- and tick-borne members of the family Flaviviridae. Orthoflaviviruses pose major public health threats,...Orthoflaviviruses - including dengue, Zika, yellow fever, Japanese encephalitis, and Powassan viruses - are mosquito- and tick-borne members of the family Flaviviridae. Orthoflaviviruses pose major public health threats, with the potential for epidemics and pandemics. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines offer a powerful platform by delivering in vitro-synthesized viral antigen-encoding mRNAs into the host, where they generate proteins that trigger robust immune responses. These synthetic platforms simplify the expression of complex viral glycoproteins, allow rapid and scalable manufacturing that is critical in a pandemic/epidemic scenario, and support multivalent designs to broaden protection. This review highlights recent advancements in mRNA vaccines for orthoflaviviruses and examines how innovations in antigen design and delivery platforms may offer broad, safe, and durable protection against diverse pathogenic orthoflaviviruses.
This essay uses immunology to illuminate human relationships. Moving beyond self/non-self toward danger-based models, it draws parallels between cytokine communication and language, tolerance and forgiveness, microbiota...This essay uses immunology to illuminate human relationships. Moving beyond self/non-self toward danger-based models, it draws parallels between cytokine communication and language, tolerance and forgiveness, microbiota diversity and coexistence. Recognizing these metaphors reveals pathways toward healthier connections within individuals, communities, and societies.
Maternal immune activation (MIA), triggered by infection or inflammation during pregnancy, is a well-recognized risk factor for neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD). Clinical cohort...Maternal immune activation (MIA), triggered by infection or inflammation during pregnancy, is a well-recognized risk factor for neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD). Clinical cohort studies and rodent models suggest that natural killer (NK) cells play a significant role in NDD pathogenesis, but the underlying mechanisms remain poorly defined. Here, we summarize the key immune mediators involved in MIA-induced NDDs, emphasizing microglia as a central hub. We then examine emerging evidence implicating aberrant NK cell activation in ASD, underscoring their overlooked contribution to impaired neurodevelopment. Finally, we discuss potential mechanisms of NK cell-microglia crosstalk in NDDs. Elucidating these interactions in the context of MIA will be crucial for developing preventive and therapeutic strategies against inflammation-driven NDDs.
Traumatic brain injury (TBI) is a leading cause of neurological disability, associated with higher rates of cognitive complications that negatively affect recovery. Myriad cytokine and chemokine pathways propagate the se...Traumatic brain injury (TBI) is a leading cause of neurological disability, associated with higher rates of cognitive complications that negatively affect recovery. Myriad cytokine and chemokine pathways propagate the secondary responses to injury. This review discusses the integration of peripheral and central immune cytokine and chemokine signaling cascades after TBI and recovery, with a focus on preclinical work. We first discuss key cytokine and chemokine interactions influencing recovery and long-term deficits. Next, we discuss the major cell types that propagate and respond to the inflammatory process after TBI. Understanding neuroimmune signaling, utilizing recent advances in transcriptomics and immune profiling, with a focus on cytokines and chemokine after TBI reveals therapeutic targets and informs strategies to improve long-term recovery and outcomes.
Sepsis, a life-threatening condition triggered by infection, disrupts the body's immune balance and remains a major global health challenge. This forum explores the dual roles of cytokines in sepsis: their overactivation...Sepsis, a life-threatening condition triggered by infection, disrupts the body's immune balance and remains a major global health challenge. This forum explores the dual roles of cytokines in sepsis: their overactivation drives 'cytokine storms,' and dysregulation leads to immunosuppression. It also discusses regulatory mechanisms for developing targeted therapies.
Trends Immunol
· 2026 Mar · PMID 41058380
·
Full text
The evolution of the fetal immune system within the womb is a delicate balancing act: it is trained to not reject maternal antigens, while equipping itself with 'learned' immunity to survive and thrive in the outside wor...The evolution of the fetal immune system within the womb is a delicate balancing act: it is trained to not reject maternal antigens, while equipping itself with 'learned' immunity to survive and thrive in the outside world. In this opinion article, we propose that a deliberate maternal touch via immune and nutritional influences, orchestrated, in part, by microbiota-derived components, imprints the fetal immune system with the needed immune memory and epigenetic marks to navigate a far less nurturing outside world, including early microbial colonizers in the newborn's intestine, pathogens and irritants, and allergens in food. We redefine the hygiene hypothesis to include prenatal maternal microbial exposures, priming fetal immune development for long-term fitness and reduced inflammatory/autoimmune disease risk.