The establishment and maintenance of immune homeostasis rely on a dynamic, bidirectional exchange of information between commensal microorganisms and the host immune system. At the center of this process are CD4+Foxp3+ regulatory T cells (Tregs), which have emerged as pivotal mediators to ensure immunological equilibrium. This review explores the sophisticated mechanisms by which the gut microbiota modulates the differentiation, expansion, and functional specialization of Tregs, orchestrating intestinal immune tolerance to support host-microbiota mutualism. We discuss the role of microbial-derived structural components and metabolites in shaping the immunoregulatory fitness of Tregs. Additionally, we explore the impact of gut microbial dysbiosis, where disrupted microbial-immune crosstalk compromises immune tolerance, contributing to the development of inflammatory and autoimmune disorders. Finally, we highlight the potential of microbiota-based strategies to recalibrate intestinal immunity and restore immune tolerance.

Regulatory T (Treg) cells play critical roles in maintaining immune tolerance and tissue homeostasis, but impede anti-tumor immunity. Recent work has established how Treg cells metabolically adapt within the tumor microenvironment (TME), and these adaptations frequently provide a functional advantage over effector T cells. Further, enhanced Treg cell function in the TME may contribute to the limited efficacy of current immunotherapies, especially immune checkpoint blockade (ICB). Here, we review recent progress in understanding mechanisms of Treg cell heterogeneity and function in tumors, with a particular focus on cellular metabolism as an underlying factor by which Treg cells are uniquely poised to thrive in the TME and contribute to tumorigenesis. We describe how cellular metabolism and nutrient or metabolic communication shape Treg cell lineage identity and function in the TME. We also discuss the interplay between ICB and Treg cell metabolism and function, and highlight current strategies targeting Treg cell metabolism specifically in the TME. Understanding metabolic control of intratumoral Treg cells provides excellent opportunities to uncover new or combination therapies for cancer.

Multiple screening approaches were carried out to identify novel chemistry starting for Pyruvate Dehydrogenase Kinases (PDHKs) inhibitors. Through hit triaging efforts and structure-based optimization, two series of ATP competitive inhibitors with single digit nanomolar enzymatic potency for PDHK1/2 and around 10-100-fold selectivity over PDHK4/3 were discovered. Approach of covalent inhibitor was explored to successfully improve the cellular target engagement to single digit micromolar range.

Glucose metabolism is a critical regulator of T cell function, largely thought to support their activation and effector differentiation. Here, we investigate how individual glycolytic reactions determine the pathogenicity of T helper 17 (Th17) cells using Compass, an algorithm we previously developed for inferring metabolic states from single-cell RNA sequencing. Surprisingly, Compass predicted that the metabolic shunt between 3-phosphoglycerate (3PG) and 2-phosphoglycerate (2PG) is inversely correlated with pathogenicity in Th17 cells. Indeed, perturbation of phosphoglycerate mutase (PGAM), the enzyme catalyzing 3PG to 2PG conversion, induces a pathogenic gene expression program by suppressing a gene module associated with the least pathogenic state of Th17 cells. Finally, PGAM inhibition in Th17 cells exacerbates neuroinflammation in the adoptive transfer model of experimental autoimmune encephalomyelitis, consistently with PGAM promoting the non-pathogenic phenotype of Th17 cells. Overall, our study identifies PGAM, contrary to other glycolytic enzymes, as a negative regulator of pathogenic Th17 cell differentiation.

Neutrophil extracellular traps (NETs) are complex, web-like structures consisting of DNA intertwined with antimicrobial proteins, which neutrophils release upon immune activation. These structures play a crucial role in pathogen elimination, particularly in infectious diseases. However, their involvement in various pathological conditions is multifaceted and context-dependent, while NETs contribute to host defense against infections, they can also exacerbate sterile inflammation, autoimmune disorders, and tumor progression. This review provides a comprehensive analysis of the molecular mechanisms governing NET formation and examines their interactions with immune cells, emphasizing how these interactions shape immune responses and drive disease dynamics. Furthermore, it explores ongoing clinical trials and emerging therapeutic strategies targeting NETs, offering critical insights into their potential translational applications in clinical practice.

Autoimmune hepatitis (AIH) is a progressive liver inflammatory disease mediated by an autoimmune response, with an increasing incidence rate. In severe cases, AIH will rapidly progress to liver cirrhosis and liver failure and even lead to death. The gut microbiota is a complex ecosystem that significantly regulates physiological and pathological processes among various digestive system diseases. It is widely acknowledged that there is a critical correlation between AIH and the gut microbiota. Numerous studies have demonstrated that the composition of gut microbiota in individuals with AIH differs markedly from that of healthy subjects. Immune cells, especially T cells, are pivotal in the development of AIH, closely interacting with the gut microbiota. In this review, we discuss the regulatory role of the gut microbiota in T cell-mediated development of AIH, as well as the effect of T cells on the composition of the gut microbiota in AIH. By modulating gut microbiota or immunity pathways, novel opportunities are provided to regulate the balance of the immune-microbial microenvironment, targeting the dual factor for autoimmune hepatitis therapies.

Mitochondria are traditionally known as the cells' powerhouses; however, their roles go far beyond energy suppliers. They are involved in intracellular signaling and thus play a crucial role in shaping cells' destiny and functionality, including immune cells. Mitochondria can be actively exchanged between immune and non-immune cells via mechanisms such as nanotubes and extracellular vesicles. The mitochondria transfer from immune cells to different cells is associated with physiological and pathological processes, including inflammatory disorders, cardiovascular diseases, diabetes, and cancer. On the other hand, mitochondrial transfer from mesenchymal stem cells, bone marrow-derived stem cells, and adipocytes to immune cells significantly affects their functions. Mitochondrial transfer can prevent exhaustion/senescence in immune cells through intracellular signaling pathways and metabolic reprogramming. Thus, it is emerging as a promising therapeutic strategy for immune system diseases, especially those involving inflammation and autoimmune components. Transferring healthy mitochondria into damaged or dysfunctional cells can restore mitochondrial function, which is crucial for cellular energy production, immune regulation, and inflammation control. Also, mitochondrial transfer may enhance the potential of current therapeutic immune cell-based therapies such as CAR-T cell therapy.

The tumor microenvironment, characterized by low oxygen tension and scarce nutrients, impairs chimeric antigen receptor (CAR)-T cell metabolism, leading to T cell exhaustion and dysfunction. Notably, Foxp3 confers a metabolic advantage to regulatory T cells under such restrictive conditions. Exploiting this property, we generated CAR-TFoxp3 cells by co-expressing Foxp3 with a third-generation CAR construct. The CAR-TFoxp3 cells exhibited distinct metabolic reprogramming, marked by downregulated aerobic glycolysis and oxidative phosphorylation coupled with upregulated lipid metabolism. This metabolic shift was driven by Foxp3's interaction with dynamin-related protein 1. Crucially, CAR-TFoxp3 cells did not acquire regulatory T cell immunosuppressive functions but instead demonstrated enhanced antitumor potency and reduced expression of exhaustion markers via Foxp3-mediated adaptation. The potent antitumor effect and absence of immunosuppression were confirmed in a humanized immune system mouse model. Our findings establish a metabolic reprogramming-based strategy to enhance CAR-T cell adaptability within the hostile tumor microenvironment while preserving therapeutic efficacy.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, offering life-saving benefits to tumor patients. However, the utilize of ICI agents is often accompanied by immune-related adverse events (irAEs), among which cardiovascular toxicities have attracted more and more attention. ICI induced cardiovascular toxicities predominantly present as acute myocarditis and chronic atherosclerosis, both of which are driven by excessive immune activation. Reprogramming of T cells and macrophages has been demonstrated as a pivotal factor in the pathogenesis of these complications. Therapeutic strategies targeting glycolysis, fatty acid oxidation, reactive oxygen species (ROS) production and some other key signaling have shown promise in mitigating immune hyperactivation and inflammation. In this review, we explored the intricate mechanisms underlying ICI-induced cardiovascular toxicities and highlighted the protective potential of immune reprogramming. We emphasize the roles of T cell and macrophage reprogramming in the heart and vasculature, showcasing their contributions to both short-term and long-term regulation of cardiovascular health. Ultimately, a deeper understanding of these processes will not only enhance the safety of ICIs but also pave the way for innovative strategies to manage immune-related toxicities in cancers therapy.

Regulation of cellular metabolism is a central element governing the fate and function of T cells. However, the in vivo metabolic characteristics of rare cells, such as nonlymphoid tissue T cells, are poorly understood because of experimental limitations. Most techniques measuring cell metabolism require large cell numbers. The recent SCENITH method allows for studying the metabolism of rare cells by flow cytometry. However, this technique requires cells to be isolated and cultured ex vivo, which may alter their metabolism. Here, we propose a new experimental approach, called in vivo SCENITH, to investigate the cellular metabolism of T cells in vivo at a steady state in the spleen and lungs. For this purpose, we administered the metabolic modulators directly in mice, instead of applying these reagents ex vivo, as in the classical SCENITH method. Whereas ex vivo manipulation impacted the viability and phenotype of T cells, this toxic effect was not observed in the in vivo SCENITH. We observed that conventional and regulatory T cells shared similar metabolic profiles. Importantly, whereas spleen T cells used both oxidative phosphorylation and glycolysis, the metabolism of T cells in the lungs was mainly based on oxidative phosphorylation. Finally, metabolic inhibitors that interfere with protein translation and energy availability downregulated Foxp3 expression in regulatory T cells. These results describe an expansion of SCENITH that allows to measure the metabolic profile of rare cells in vivo, revealing a high dependence on oxidative phosphorylation of lung T cells.

Protective immunity, essential for brain maintenance and repair, may be compromised in Alzheimer's disease (AD). Here, using high-dimensional single-cell mass cytometry, we find a unique immunometabolic signature in circulating CD4+ T cells preceding symptom onset in individuals with familial AD, featured by the elevation of CD38 expression. Using female 5xFAD mice, a mouse model of AD, we show that treatment with an antibody directed to CD38 leads to restored metabolic fitness, improved cognitive performance, and attenuated local neuroinflammation. Comprehensive profiling across distinct immunological niches in 5xFAD mice, reveals a high level of disease-associated CD4+ T cells that produce IL-17A in the dural meninges, previously linked to cognitive decline. Targeting CD38 leads to abrogation of meningeal TH17 immunity and cortical IL-1β, breaking the negative feedback loop between these two compartments. Taken together, the present findings suggest CD38 as an immunometabolic checkpoint that could be adopted as a pre-symptomatic biomarker for early diagnosis of AD, and might also be therapeutically targeted alone or in combination with other immunotherapies for disease modification.

The "Warburg effect" is a term coined a century ago for the preferential use of glycolysis over aerobic respiration in tumor cells for energy production, even under aerobic conditions. Although this is a less efficient mechanism of generating energy from glucose, aerobic glycolysis, in addition to the canonical anaerobic glycolysis, is an effective means of lactate production. The abundant waste product, lactate, yielded by the dual glycolysis in a tumor, has been discovered to be a major biomolecule that drives cancer progression. Lactate is a metabolic energy source that, via cell membrane lactate transporters, shuttles in and out of cancer cells as well as cancer cell-associated stromal cells and immune cells within the tumor microenvironment (TME). Additionally, lactate serves as a pH tuner, signaling ligand and transducer, epigenetic and gene transcription regulator, TME modifier, immune suppressor, chemoresistance modulator, and prognostic marker. With such broad functionalities, the production-consumption-reproduction of TME lactate fuels tumor growth and dissemination. Here, we elaborate on the lactate sources that contribute to the pool of lactate in the TME, the functions of TME lactate, the influence of the TME lactate on immune cell function and local tissue immunity, and anticancer therapeutic approaches adopting lactate manipulations and their efficacies. By scrutinizing these properties of the TME lactate and others that have been well addressed in the field, it is expected that a better weighing of the influence of the TME lactate on cancer development, progression, prognosis, and therapeutic efficacy can be achieved.

Andrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4+ IL-17A+ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.

Premature infants are highly susceptible to infections that can lead to sepsis with life-threatening organ dysfunctions. The clinical practice of high parenteral glucose supply in preterm infants can exacerbate infection outcomes through excessive glycolysis-induced inflammatory response. This in turn can affect the health of vital preterm organs, including the brain and kidneys. We hypothesized that reduced parenteral glucose supply to infected preterm newborns may help protect against pathology in these two key organs.

Cesarean-delivered preterm pigs were nourished with high or low parenteral glucose levels (21 % vs. 5 %), infused with Staphylococcus epidermidis or saline, and monitored in heated, oxygenated incubators until 22 h. Blood, brain, and kidney samples were collected for histological, immunohistological, q-PCR, ELISA, and biochemical analyses.

Infection led to multiple pathological changes (e.g. edema), increased inflammation and tissue injury (indicated by gene expression data) in both brain and kidneys of preterm piglets. Reduced glucose supply in infected animals alleviated histopathological manifestations in the brain, and reduced neuroinflammation with enhanced M2 microglial phenotype. Reduced glucose supply also decreased plasma creatinine, and the severity of renal edema, tubular vacuolization and dilatation. Multiple genes related to innate and Th1 immunity in both organs were dampened by reduced glucose supply. Correlation analysis showed that renal inflammation was more closely connected to systemic inflammation compared to neuroinflammation.

Reduced glucose supply can reduce renal and neuro-inflammation during neonatal infection, thereby protecting brain and kidney health in infected preterm neonates.

Cellular therapies are living drugs whose efficacy depends on persistence and survival. Expansion of therapeutic T cells employs hypermetabolic culture conditions to promote T cell expansion. We show that typical in vitro expansion conditions generate metabolically and functionally impaired T cells more reliant on aerobic glycolysis than those expanding in vivo. We used dichloroacetate (DCA) to modulate glycolytic metabolism during expansion, resulting in elevated mitochondrial capacity, stemness, and improved antitumor efficacy in murine T cell receptor (TCR)-Tg and human CAR-T cells. DCA-conditioned T cells surprisingly show no elevated intratumoral effector function but rather have improved engraftment. DCA conditioning decreases reliance on glucose, promoting usage of serum-prevalent physiologic carbon sources. Further, DCA conditioning promotes metabolic flux from mitochondria to chromatin, resulting in increased histone acetylation at key longevity genes. Thus, hyperglycemic culture conditions promote expansion at the expense of metabolic flexibility and suggest pharmacologic metabolic rewiring as a beneficial strategy for improvement of cellular immunotherapies.

T cell metabolism and differentiation significantly shape the initiation, progression, and resolution of inflammatory responses. Upon activation, T cells undergo extensive metabolic shifts to meet distinct functional demands across various inflammatory stages. These metabolic alterations are not only critical for defining different T cell subsets, but also for sustaining their activity in inflammatory environments. Key signaling pathways-including mTOR, HIF-1α, and AMPK regulate these metabolic adaptions, linking cellular energy states with T cell fate decisions. Insights into the metabolic regulation of T cells offer potential therapeutic strategies to manipulate T cell function, with implications for treating autoimmune diseases, chronic inflammation, and cancer by targeting specific metabolic pathways.

The abnormal effector function of CD4+ T cells plays a key role in the pathogenesis of Sjogren's syndrome (SS) and its associated systematic autoimmune response. Cellular metabolism, including glucose metabolism, lipid metabolism and amino acid metabolism, supports proliferation, migration, survival and differentiation into distinct CD4+ T-cell subsets. Different subtypes of T cells have significantly different demands for related metabolic processes, which enables us to finely regulate CD4+ T cells through different metabolic processes in autoimmune diseases such as SS. In this review, we summarize the effects of disturbances in distinct metabolic processes, such as glycolysis, fatty acid metabolism, glutamine decomposition, mitochondrial dynamics, and ferroptosis, on how to support the effector functions of CD4+ T cells in the SS. We also discuss potential drugs with high value in the treatment of SS through metabolic normalization in CD4+ T cells. Finally, we propose possible directions for future targeted therapy for immunometabolism in SS.

The transcription factor interferon regulatory factor 4 (IRF4) is crucial for the fate determination of pro-inflammatory T helper (Th) 17 and the functionally opposing group of immunomodulatory regulatory T (Treg) cells. However, the molecular mechanisms of how IRF4 steers diverse transcriptional programs in Th17 and Treg cells are far from being definitive. Here, we integrated data derived from affinity-purification and full mass-spectrometry-based proteome analysis with chromatin immunoprecipitation sequencing. This allowed the characterization of subtype-specific molecular programs and the identification of IRF4 interactors in the Th17/Treg context. Our data reveal that IRF4-interacting transcription factors are recruited to IRF composite elements for the regulation of cell-type-specific transcriptional programs as exemplarily demonstrated for FLI1, which, in cooperation with IRF4, promotes Th17-specific gene expression. FLI1 inhibition markedly impaired Th17 differentiation. The present "omics" dataset provides a valuable resource for studying IRF4-mediated gene regulatory programs in pro- and anti-inflammatory immune responses.

Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.

Lactate, the end product of both anaerobic and aerobic glycolysis in proliferating and growing cells-with the latter process known as the Warburg effect-is historically considered a mere waste product of cell and tissue metabolism. However, research over the past ten years has unveiled multifaceted functions of lactate that critically shape and impact cellular biology. Beyond serving as a fuel source, lactate is now known to influence gene expression through histone modification and to function as a signaling molecule that impacts a wide range of cellular activities. These properties have been particularly studied in the context of both adaptive and innate immune responses. Here, we review the diverse roles of lactate in the regulation of the immune system during homeostasis and disease pathogenesis (including cancer, infection, cardiovascular diseases, and autoimmunity). Furthermore, we describe recently proposed therapeutic interventions for manipulating lactate metabolism in human diseases.

Membranous nephropathy (MN) is a primary glomerular disease commonly causing adult nephrotic syndrome. Characterized by thickened glomerular capillary walls due to immune complex deposition, MN is a complex autoimmune disorder. Its pathogenesis involves immune deposit formation, complement activation, and a heightened risk of renal failure. Central to MN is immune system dysfunction, particularly the dysregulation of B and T cell responses. B cells contribute to renal injury through the production of autoantibodies, particularly IgG targeting the phospholipase A2 receptor (PLA2R) on podocytes, while T cells modulate immune responses that influence disease progression. Metabolic reprogramming alters lymphocyte survival, differentiation, proliferation, and function, potentially triggering autoimmune processes. Although the link between immune cell metabolism and MN remains underexplored, this review highlights recent advances in understanding immune metabolism and its role in MN. These insights may provide novel biomarkers and therapeutic strategies for MN treatment.

Fevers are an ancient feature of the inflammatory microenvironment. While fevers may improve the immune response to pathogens, mechanisms are unclear. We explore recent studies of how fever-range temperatures inform mammalian T cell metabolism, differentiation, and stress responses. Recent evidence indicates that metabolic programs initiated by fever are maintained upon return to thermo-normality, potentially providing a lasting benefit. Despite its impact, temperature remains overlooked and warrants further study. This is especially apparent when considering the wide temperature differential between tissues within the body and during inflammatory disease progression. We propose that differences in the metabolic and stress responses between T cell subsets upon thermal stress contribute to determining immune cell makeup and fate during inflammation.

It is widely acknowledged that dietary habits have profound impacts on human health and diseases. As the most important sweeteners and energy sources in human diets, hexoses take part in a broad range of physiopathological processes. In recent years, emerging evidence has uncovered the crucial roles of hexoses, such as glucose, fructose, mannose, and galactose, in controlling the differentiation or function of immune cells.

Herein, we reviewed the latest research progresses in the hexose-mediated modulation of immune responses, provided in-depth analyses of the underlying mechanisms, and discussed the unresolved issues in this field.

Owing to their immunoregulatory effects, hexoses affect the onset and progression of various types of immune disorders, including inflammatory diseases, autoimmune diseases, and tumor immune evasion. Thus, targeting hexose metabolism is becoming a promising strategy for reversing immune abnormalities in diseases.

Aberrant autoreactive innate and adaptive immune responses cause systemic autoimmune diseases. Autoimmunity has been linked to abnormal metabolic states, and immunometabolism has emerged as a critical field in understanding the pathogenesis of rheumatic diseases. We aimed to explore the latest research on metabolic reprogramming in various immune cell types, including T cells, B cells, neutrophils, dendritic cells, monocytes, and macrophages, in the context of rheumatic diseases.

Each immune cell utilizes preferred metabolic pathways, and the cell activation dramatically modifies metabolic status. The inhibition of these pathways alters cell survival, differentiation, proliferation, and cytokine production - all of which contribute to rheumatic disease progression.

Targeting metabolic pathways or introducing anti-inflammatory metabolites, such as itaconate, could be novel therapeutic strategies for rheumatic diseases. Further research should focus on strategies for translating basic research findings to bedside applications.

In this special issue to celebrate the 30th anniversary of the Uruguayan Society for Neuroscience (SNU), we find it pertinent to highlight that research on glial cells in Uruguay began almost alongside the history of SNU and contributed to the understanding of neuron-glia interactions within the international scientific community. Glial cells, particularly astrocytes, traditionally regarded as supportive components in the central nervous system (CNS), undergo notable morphological and functional alterations in response to neuronal damage, a phenomenon referred to as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function, given the high energy demand of the nervous system. Although astrocytes are typically considered to exhibit low mitochondrial respiratory chain activity, they possess a noteworthy mitochondrial network. Interestingly, both the morphology and activity of these organelles change following glial reactivity. Despite receiving less attention compared to studies on neuronal mitochondria, recent studies indicate that mitochondria play a crucial role in driving the transition of astrocytes from a quiescent to a reactive state in various neurological disorders. Notably, stimulating mitochondria in astrocytes has been shown to reduce damage associated with the neurodegenerative disease amyotrophic lateral sclerosis. Here, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage. In this review, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.

Regulatory T (Treg) cells are essential for maintaining immune homeostasis by suppressing excessive immune responses. In the context of cancer, however, Tregs promote immune evasion and tumor progression, particularly through their unique adaptations within the tumor microenvironment (TME). Recent research has emphasized how metabolic characteristics shape Treg activation, migration, and immunosuppressive function, revealing the impact of metabolic pathways on Treg fitness in homeostasis and within the TME. In this review, we first provide an overview of Tregs in cancer immunology, discussing their immunosuppressive roles and properties specific to the TME. We then examine the metabolic requirements for Treg activation and migration under normal conditions, followed by a discussion of how hypoxia, lactate accumulation, nutrient limitation, oxidative stress, and other TME-specific factors alter Treg metabolism and contribute to cancer immune evasion. Finally, we explore therapeutic strategies that target Treg metabolism within the TME, including pharmacological modulation of specific metabolic pathways to diminish Treg-mediated immunosuppression. Thus, we could suggest future directions and clinical implications for Treg-targeted metabolic modulation as a complementary approach in cancer treatment, setting the stage for novel strategies in immunotherapy.

Immunometabolism is an emerging field that explores the intricate interplay between immune cells and metabolism. Regulatory T cells (Tregs), which maintain immune homeostasis in immunometabolism, play crucial regulatory roles. The activation, differentiation, and function of Tregs are influenced by various metabolic pathways, such as the Mammalian targets of rapamycin (mTOR) pathway and glycolysis. Correspondingly, activated Tregs can reciprocally impact these metabolic pathways. Tregs also possess robust adaptive capabilities, thus enabling them to adapt to various microenvironments, including the tumor microenvironment (TME). The complex mechanisms of Tregs in metabolic diseases are intriguing, particularly in conditions like MASLD, where Tregs are significantly upregulated and contribute to fibrosis, while in diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), they show downregulation and reduced anti-inflammatory capacity. These phenomena suggest that the differentiation and function of Tregs are influenced by the metabolic environment, and imbalances in either can lead to the development of metabolic diseases. Thus, moderate differentiation and inhibitory capacity of Tregs are critical for maintaining immune system balance. Given the unique immunoregulatory abilities of Tregs, the development of targeted therapeutic drugs may position them as novel targets in immunotherapy. This could contribute to restoring immune system balance, resolving metabolic dysregulation, and fostering innovation and progress in immunotherapy.

Food allergies are pathological adverse reactions against harmless dietary proteins. While studies have shown the involvement of host metabolic changes (e.g., lipid metabolism and amino acid metabolism) in the development of food allergy (FA), the adaptive changes in glucose metabolism induced by food allergen exposure remain largely unclear. In this study, BALB/c mice were sensitized intraperitoneally with an ovalbumin (OVA)/aluminum adjuvant, followed by oral OVA challenges to induce anaphylaxis. Increased levels of serum OVA-specific IgE and MCPT-1, and Th2 response bias were also presented in FA mice. Subsequently, the intestinal untargeted metabolomic analysis revealed the signature enrichment of glycolysis, manifested by increases in glycolytic metabolites including glucose-6-phosphate, fructose-6-phosphate, 2-phosphoglycerate, and lactate in FA mice. Consistently, the serum lactate level was found to be significantly elevated in allergic mice. Oral administration of OVA also upregulated the expression of critical metabolic enzymes in glycolysis, namely hexokinase 2, phosphoglycerate mutase 1, and lactate dehydrogenase. Moreover, the hypoxia inducible factor-1 (HIF-1) signaling pathway was activated in FA mice, and the expression of HIF-1α, known as the upstream regulator of glycolysis, was increased after oral OVA challenges. In vitro inhibition of HIF-1α was found to impede mast cell inflammatory responses to allergens. In summary, this study demonstrated that OVA-induced FA exhibited a glucose metabolic feature of HIF-1α-mediated glycolysis upregulation, suggesting the potential of HIF-1α/glycolysis targeted strategies in the alleviation of FA.

Glucose deprivation inhibits T-cell metabolism and function. Glucose levels are low in the tumor microenvironment of solid tumors and insufficient glucose uptake limits the antitumor response of T cells. Furthermore, glucose restriction can contribute to the failure of chimeric antigen receptor T (CAR-T) cell therapy for solid tumors. However, the impact of glucose restriction remains unknown in CAR-T cell therapy.

Glucose transporters were detected and overexpressed in CAR-T cells. The impacts of glucose restriction on CAR-T cells were checked in vitro and in vivo.

Glucose restriction significantly decreased CAR-T cell activation, effector function, and expansion. CAR-T cells expressed high levels of the glucose transporter Glut1, which has a low affinity for glucose. Overexpression of Glut1 failed to improve CAR-T cell function under glucose-restricted conditions. In contrast, the function and antitumor potential of CAR-T cells was enhanced by the overexpression of Glut3, which has the highest affinity for glucose among the Glut transporter family and is expressed in minor parts of CAR-T cells. Glut3-overexpressing CAR-T cells demonstrated increased tumoricidal efficacy in multiple xenografts and syngenetic mouse models. Furthermore, Glut3 overexpression activated the PI3K/Akt pathway and increased OXPHOS and mitochondrial fitness.

We provide a direct and effective approach to enhance low glucose uptake levels by CAR-T cells and improve their antitumor efficacy against solid tumors.

Malignant brain tumors are among the most lethal cancers. Recent studies emphasized the crucial involvement of the immune system, especially T cells, in driving tumor progression and influencing patient outcomes. The emerging field of immunometabolism has shown that metabolic pathways play a pivotal role in regulating immune responses within the tumor microenvironment. This study aims to clarify the relationships between specific T cell phenotypes, circulating metabolites, and malignant brain tumors.

We utilized a multiple mendelian randomization approach to investigate the associations between T cell phenotypes and malignant brain tumors, as well as the role of plasma metabolites in mediating these interactions. Instrumental variables were selected based on stringent criteria, and multiple mendelian randomization methods were utilized to identify causal pathways and metabolites potentially mediating these effects.

Our analysis identified significant associations between seven distinct T cell phenotypes, including various CD8 + and regulatory T cell subsets, and the presence of malignant brain tumors. We also identified 87 plasma metabolites correlated with these tumors. Notably, metabolites such as octadecanedioylcarnitine (C18-DC) and eicosanedioate (C20-DC) were implicated in modulating the risk of developing malignant brain tumors. Furthermore, metabolites such as 5-dodecenoate (12:1n7) and arachidonate (20:4n6) were found to influence tumor risk, particularly in relation to CD28 - CD8 + T cells.

The study identifies key T cell phenotypes and plasma metabolites involved in the pathogenesis of malignant brain tumors, offering potential biomarkers and therapeutic targets for future interventions.

Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis and preventing autoimmune diseases. Recent advances in immunometabolism have revealed the pivotal role of mitochondrial dynamics and metabolism in shaping Treg functionality. Tregs depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to support their suppressive functions and long-term survival. Mitochondrial processes such as fusion and fission significantly influence Treg activity, with mitochondrial fusion enhancing bioenergetic efficiency and reducing reactive oxygen species (ROS) production, thereby promoting Treg stability. In contrast, excessive mitochondrial fission disrupts ATP synthesis and elevates ROS levels, impairing Treg suppressive capacity. Furthermore, mitochondrial ROS act as critical signaling molecules in Treg regulation, where controlled levels stabilize FoxP3 expression, but excessive ROS leads to mitochondrial dysfunction and immune dysregulation. Mitophagy, as part of mitochondrial quality control, also plays an essential role in preserving Treg function. Understanding the intricate interplay between mitochondrial dynamics and Treg metabolism provides valuable insights for developing novel therapeutic strategies to treat autoimmune disorders and enhance immunotherapy in cancer.

Inflammatory environments induce the generation of dysfunctional IFNγ+T-bet+FOXP3+ Th1-like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1-like Tregs are not well understood. Sphingosine-1-phosphate (S1P) signalling molecules are upregulated in Th1-like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by FTY720 inhibits the generation of Th1-like Tregs and rescues their suppressive function. These effects are mediated by a decrease in mTORC1 signalling and reversal of the mitochondrial uncoupling that Tregs undergo during their reprogramming into Th1-like Tregs in vitro. Finally, these results are validated in in vivo-generated Th1-like Tregs, as Tregs from MS patients treated with FTY720 display decreased Th1-like Treg frequency, increased suppressive function and mitochondrial metabolism rebalance. These results highlight the involvement of mitochondrial uncoupling in Treg reprogramming and identify S1P signalling inhibition as a target to suppress the generation of dysfunctional Th1-like Tregs.

Immune system functions play crucial roles in both health and disease, and these functions are regulated by their metabolic programming. The field of immune engineering has emerged to develop therapeutic strategies, including polymeric nanoparticles (NPs), that can direct immune cell phenotype and function by directing immunometabolic changes. Precise control of bioenergetic processes may offer the opportunity to prevent undesired immune activity and improve disease-specific outcomes. In this review we discuss the role that polymeric NPs can play in shaping immunometabolism and subsequent immune system activity through particle-mediated delivery of metabolically active agents as either structural components or cargo.

Dysregulation of Th17 and Treg cells contributes to the pathophysiology of cerebral ischemia. Metabolic changes of peripheral CD4+ T cells lead to the imbalance of Treg/Th17 polarization, which represents a promising strategy for post-stroke therapy. Polyphyllin VII (PVII), a steroidal saponin extracted from traditional Chinese herb Rhizoma Paridis, has multiple bioactivities, but the potential function of PVII in cerebral ischemia-reperfusion injury is not elucidated yet. In our study, a mouse transient middle cerebral artery occlusion (MCAO) model was constructed. TTC staining, H&E staining, TUNEL staining, ELISA assay, flow cytometry, western blot, RT-qPCR, Open-field test, Morris water maze test, hanging wire test, rotarod test and foot-fault test were performed to evaluate the potential function of PVII in MCAO mice. We found that PVII showed protective effects on cerebral ischemia-reperfusion injury by reducing infarct volume, ameliorating brain injury and neuroinflammation, and improving long-term functional recovery of MCAO mice. PVII promoted Treg infiltration and suppressed infiltration of Th1/Th17 cells in ischemic brain in vivo. Moreover, PVII impaired peripheral CD4+ T cell activation and modulated Treg/Th17 differentiation in vitro. Mechanistically, PVII suppressed mTORC1 activation to influence glycolytic metabolism and ROS generation of T cells, thus leads to the imbalance of Treg/Th17 polarization towards Treg skewed. Furthermore, reactivation of mTORC1 by MHY1485 abolished the influence of PVII on brain injury and neuroinflammation in MCAO mice. Our data provided a novel role of PVII in cerebral ischemia-reperfusion injury via manipulating Treg/Th17 imbalance.

Although tumor necrosis factor receptor 2 (TNFR2) has been recognized as an attractive next-generation candidate target for cancer immunotherapy, the factors that regulate the gene expression and their mechanistic effects on tumor-infiltrating regulatory T cells (Treg cells) remain poorly understood.

Single-cell RNA sequencing analysis was employed to analyze the phenotypic and functional differences between TNFR2+ Treg cells and TNFR2- Treg cells. Malignant pleural effusion (MPE) from humans and mouse was used to investigate the potential mechanisms by which lactate regulates TNFR2 expression.

Treg cells with high TNFR2 expression exhibited elevated levels of immune checkpoint molecules. Additionally, the high expression of TNFR2 on Treg cells was positively correlated with a poor prognosis in MPE patients. Moreover, we revealed that lactate upregulated TNFR2 expression on Treg cells, thereby enhancing their immunosuppressive function in MPE. Mechanistically, lactate modulated the gene transcription of transcription factor nuclear factor-κB p65 (NF-κB p65) through histone H3K18 lactylation (H3K18la), subsequently upregulating the gene expression of TNFR2 and expediting the progression of MPE. Notably, lactate metabolism blockade combined with immune checkpoint blockade (ICB) therapy effectively enhanced the efficacy of ICB therapy, prolonged the survival time of MPE mice, and improved immunosuppression in the microenvironment of MPE.

The study explains the mechanism that regulates TNFR2 expression on Treg cells and its function in MPE progression, providing novel insights into the epigenetic regulation of tumor development and metabolic strategies for MPE treatment by targeting lactate metabolism in Treg cells.

Ferroptosis is a novel form of cell death characterized by unlimited accumulation of iron-dependent lipid peroxides. It is often accompanied by disease, and the relationship between ferroptosis of immune cells and immune regulation has been attracting increasing attention. Initially, it was found in cancer research that the inhibition of regulatory T cell (Treg) ferroptosis and the promotion of CD8+ T cell ferroptosis jointly promoted the formation of an immune-tolerant environment in tumors. T-cell ferroptosis has subsequently been found to have immunoregulatory effects in other diseases. As an autoimmune disease characterized by immune imbalance, T-cell ferroptosis has attracted attention for its potential in regulating immune balance in lupus nephritis. This article reviews the metabolic processes within different T-cell subsets in lupus nephritis (LN), including T follicular helper (TFH) cells, T helper (Th)17 cells, Th1 cells, Th2 cells, and Treg cells, and reveals that these cellular metabolisms not only facilitate the formation of a T-cell immune imbalance but are also closely associated with the occurrence of ferroptosis. Consequently, we hypothesize that targeting the metabolic pathways of ferroptosis could become a novel research direction for effectively treating the immune imbalance in lupus nephritis by altering T-cell differentiation and the incidence of ferroptosis.