Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.

Eukaryotes possess chromosome ends known as telomeres. As telomeres shorten, organisms age, a process defined as senescence. Although uncontrolled telomere lengthening has been naturally connected with cancer developments and immortalized state, many cancers are instead characterized by extremely short, genomically unstable telomeres that may hide cancer cells from immune attack. By contrast, other malignancies feature extremely long telomeres due to absence of 'shelterin' end cap protecting factors. The reason for rampant telomere extension in these cancers had remained elusive. Hence, while telomerase supports tumor progression and escape in cancers with very short telomeres, it is possible that different - transfer based or alternative - lengthening pathways be involved in the early stage of tumorigenesis, when telomere length is intact. In this Review, I hereby discuss recent discoveries in the field of telomeres and highlight unexpected links connecting cancer and telomere state. We hope these parallelisms may inform new therapies to eradicate cancers.

The term metabolism refers to the multi-faceted biochemical reactions within a cell or an organism that occur to maintain energy homeostasis, cell growth, and oxidative balance. Cells possess a high metabolic plasticity, allowing them to adapt to the dynamic requirements of their functional state and environment. Deregulated cellular metabolism is a hallmark of many diseases, including benign and malignant hematological conditions. In the last decade, multiple technological innovations in the metabolism field have made in-depth metabolic analysis broadly applicable. Such studies are shedding new light on normal and malignant hematopoiesis and open avenues to a better understanding of the biology of hematological diseases. In this review, we will first give a brief overview of central metabolic processes. Furthermore, we discuss the most commonly used methods to study metabolism. We begin by elaborating on the use of next-generation sequencing to detect metabolism-related genomic mutations and study transcriptional signatures. Furthermore, we discuss methods for measuring protein expression, such as mass spectrometry (MS), flow cytometry, and cytometry time-of-flight. Next, we describe the use of nuclear magnetic resonance spectroscopy, MS, and flow cytometry for metabolite quantification. Finally, we highlight functional assays to probe metabolic pathways in real-time. We illustrate how these technologies and their combination have advanced our understanding of the role of metabolism. Our goal is to provide hematologists with a comprehensive guide to modern techniques in metabolism research, their benefits and disadvantages, and how they guide our understanding of disease and potentially future personalized therapy decisions.

Despite current technological advancements in the treatment of glioma, immediate alleviation of symptoms can be catered by therapeutic modalities, including surgery, chemotherapy, and combinatorial radiotherapy that exploit aberrations of glioma. Additionally, a small number of target antigens, their heterogeneity, and immune evasion are the potential reasons for developing targeted therapies. This oncologic milestone has catalyzed interest in developing immunotherapies against Glioblastoma to improve overall survival and cure patients with high-grade glioma. The next-gen CAR-T Cell therapy is one of the effective immunotherapeutic strategies in which autologous T cells have been modified to express receptors against GBM and it modulates cytotoxicity.

In this review article, we examine preclinical and clinical outcomes, and limitations as well as present cutting-edge techniques to improve the function of CAR-T cell therapy and explore the possibility of combination therapy.

To date, several CAR T-cell therapies are being evaluated in clinical trials for GBM and other brain malignancies and multiple preclinical studies have demonstrated encouraging outcomes.

CAR-T cell therapy represents a promising therapeutic paradigm in the treatment of solid tumors but a few limitations include, the blood-brain barrier (BBB), antigen escape, tumor microenvironment (TME), tumor heterogeneity, and its plasticity that suppresses immune responses weakens the ability of this therapy. Additional investigation is required that can accurately identify the targets and reflect the similar architecture of glioblastoma, thus optimizing the efficiency of CAR-T cell therapy; allowing for the selection of patients most likely to benefit from immuno-based treatments.

Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia (CLL), where acquired immune dysfunction prevails. In CLL, disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation. Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells, yet its role in CLL remains unexplored. This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors, revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation. Using multi-omics and functional assays, we found that T cells present in viably frozen samples of patients with CLL (CLL T cells) showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors. CLL T cells exhibited altered lipid storage, with increased triacylglycerols and decreased cholesterol, and inefficient fatty acid oxidation (FAO). Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders. Reduced FAO was associated with lower T-cell activation but did not affect proliferation. This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL. CLL T cells displayed fewer and less clustered lipid rafts, potentially explaining the impaired immune synapse formation observed in these patients. Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells, underscoring the pivotal role of cholesterol in T-cell proliferation. This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL, presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.

NF-κB is a crucial transcription factor in lymphocyte signaling. It is activated by environmental cues that drive lymphocyte differentiation to combat infections and cancer. As a key player in inflammation, NF-κB also significantly impacts autoimmunity and transplant rejection, making it an important therapeutic target. While the signaling molecules regulating this pathway are well-studied, the effect of changes in NF-κB signaling levels on T lymphocyte differentiation, fate, and function is not fully understood. Advances in computational biology and new NF-κB-inducible animal models are beginning to clarify these questions. In this review, we highlight recent findings related to T cells, focusing on how environmental cues affecting NF-κB signaling levels determine T cell fate and function.

Benzimidazoles are the most frequently prescribed therapeutic options for treating trichinellosis in clinical settings; however, they have a lot of disadvantages. Therefore, researchers are focusing on the hunt for substitute chemicals. The goal of the current study was to compare the effectiveness of albendazole and the anti-diabetic medication metformin loaded on chitosan nanoparticles in treating mice infected with various stages of T. spiralis infection. 160 mice were included in the present study and divided into 8 groups: 6 experimentally treated groups, and positive and negative control groups. For studying the intestinal and parenteral phase, each group was broken into two more subgroups (a and b) according to the time of drug administration. The effects of albendazole, albendazole-loaded NPs, metformin, metformin-loaded NPs, combined albendazole and metformin, and metformin and albendazole-loaded NPs were assessed using parasitological studies, histopathological examination, and ultrastructural examination using SEM.Statistically significant differences were detected in all studied subgroups compared to the control infected subgroup both in the intestinal and muscular phases. The greatest decrease in recovered adult worm and muscle larvae numbers was achieved by ABZ & MET/ Cs NPs. These findings were confirmed by histopathological examination. SEM examination of the tegument of T. spirals adult worms and muscle larvae showed destruction with multiple degenerative changes.Our results suggested that metformin and its combination with albendazole especially when loaded on chitosan nanoparticles could be potential therapeutic alternative drugs against trichinellosis.

Short-lived effector cells are characterized metabolically by a highly glycolytic state, driving energy and biomass acquisition, whereas memory-fated T cells have historically been described as meeting these requirements through mitochondrial metabolism. Here, we show that the mitochondrial protein optic atrophy 1 (OPA1) is critical for rapidly dividing CD8 T cells in vivo, the requirement for which is most pronounced in effector CD8 T cells. More specifically, OPA1 supports proper cell cycle initiation and progression and the viability and survival of CD8 T cells during clonal expansion. Use of mice deficient in the mitochondrial membrane fusion proteins Mitofusin 1 and 2 (MFN1/2) in both in vivo proliferation/differentiation assays and ex vivo metabolic analysis indicates that the requirement for OPA1 during cell division supersedes its role in mitochondrial fusion. We conclude that OPA1 is critical for the generation and accumulation of short-lived effector cells that arise during the response to infection.

T cells play a central role in anti-tumor immunity, yet their function is often compromised within the immunosuppressive tumor microenvironment, leading to cancer progression and resistance to immunotherapies. T-cell activation and differentiation require dynamic metabolic shifts, with mitochondrial metabolism playing a crucial role in sustaining their function. Research in cancer immunometabolism has revealed key mitochondrial abnormalities in tumor-infiltrating lymphocytes, including reduced mitochondrial capacity, depolarization, structural defects, and elevated reactive oxygen species. While these mitochondrial disruptions are well-characterized in solid tumors and linked to T-cell exhaustion, their impact on T-cell immunity in lymphoproliferative disorders remains underexplored. Chronic lymphocytic leukemia (CLL), the most prevalent chronic adult leukemia, is marked by profound T-cell dysfunction that limits the success of adoptive cell therapies. Emerging studies are shedding light on the role of mitochondrial disturbances in CLL-related T-cell dysfunction, but significant knowledge gaps remain. This review explores mitochondrial metabolism in T-cell exhaustion, emphasizing recent findings in CLL. We also discuss therapeutic strategies to restore T-cell mitochondrial function and identify key research gaps.

Head and neck squamous cell carcinoma (HNSCC) remains a significant clinical challenge due to its aggressive behavior and poor prognosis, making the development of novel therapeutics with enhanced efficacy and minimal side effects critical. Metformin, a widely used antidiabetic agent, has recently emerged as a potential adjunctive therapy for HNSCC, exhibiting both direct anti-tumor and immunomodulatory effects. This review comprehensively explores the multifaceted role of metformin in shaping the tumor immune microenvironment within HNSCC. We emphasize its pivotal role in modulating immune cell populations and its potential for synergistic action with immunotherapeutic strategies. Furthermore, we address the current challenges associated with optimizing dosing regimens, identifying predictive biomarkers, and integrating metformin with immunotherapy. By dissecting these aspects, this review aims to pave the way for the development of personalized HNSCC treatment strategies that fully exploit the therapeutic potential of metformin.

Hashimoto's thyroiditis (HT) is the most common autoimmune thyroid disease (AITD), which is distinguished by high thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TgAb). The differentiation of CD4+T cell subsets in patients with HT is imbalanced, with Treg cells decreased and Th17 cells abnormally activated. Fatty acid oxidation supports the differentiation of Th17 cells and induces inflammation, but the specific mechanism is still unknown. This study aimed to explore the role of fatty acid oxidation and its pathway in the pathogenesis of autoimmune thyroiditis and the immune mechanism.

In in vitro experiments, a total of 60 HT patients and 20 healthy controls were selected and their CD4+T cells were sorted by magnetic beads. All 80 samples were divided into 4 groups on average: HC group (Healthy control group), HT group (Hashimoto thyroiditis CD4+T cell inactive group), TCC group(Hashimoto thyroiditis CD4+T cell activation), TCC + ETO group(Hashimoto thyroiditis CD4+T cell activation + Etomoxir group). In in vivo experiments, the mice were randomly divided into 3 groups: Con group(Control group), mTg group (CBA/J mice were injected with mTg for modeling, that is EAT mice group), and mTg + ETO group (Etomoxir intervention in EAT mice group). Fatty acid oxidation substrates of CD4+T cells in human peripheral blood were detected by targeted metabolomics. The expressions of key fatty acid oxidation proteins mTOR, ACC1 and CPT1A were detected by Western blotting. The proportion of CD4+T cell subtype differentiation in human and mouse models was detected by flow cytometry. The severity of EAT was detected by HE staining.

Compared with healthy controls, the level of CPT1A in CD4+T cells of HT patients was increased, and the intracellular fatty acid content was significantly decreased, indicating that the level of fatty acid oxidation was enhanced in HT patients. After adding Etomoxir, the level of fatty acid oxidation was significantly inhibited, and the imbalance of CD4+T cell subpopulation differentiation in HT patients was reversed. In EAT mice, the mTOR/ACC1/CPT1A pathway was significantly activated, and its expression level was decreased after adding Etomoxir. At the same time, Etomoxir could reverse the reprogramming of abnormal metabolism in EAT mice cells, reduce the spleen index, and improve lymphocyte infiltration in the thyroid.

The mTOR/ACC1/CPT1A fatty acid oxidation pathway of CD4+T cells in Hashimoto's thyroiditis was increased, and treatment with Etomoxir could inhibit the activation of this pathway, and reverse the reprogramming of abnormal metabolism in CD4+T cells, thereby reducing Hashimoto's thyroiditis.

T cells play a central role in the cancer immunity cycle. The therapeutic outcomes of T cell-based intervention strategies are determined by multiple factors at various stages of the cycle. Here, we summarize and discuss recent advances in T cell immunotherapy and potential barriers to it within the framework of the cancer immunity cycle, including T-cell recognition of tumor antigens for activation, T cell trafficking and infiltration into tumors, and killing of target cells. Moreover, we discuss the key factors influencing T cell differentiation and functionality, including TCR stimulation, costimulatory signals, cytokines, metabolic reprogramming, and mechanistic forces. We also highlight the key transcription factors dictating T cell differentiation and discuss how metabolic circuits and specific metabolites shape the epigenetic program of tumor-infiltrating T cells. We conclude that a better understanding of T cell fate decision will help design novel strategies to overcome the barriers to effective cancer immunity.

Perturbation of the mechanistic target of rapamycin (mTOR) pathway can instruct effector versus memory cell fate of tumor antigen-specific T cells in preclinical models. In this study, we sought to understand the impact of rapamycin (sirolimus), an mTOR inhibitor, on reprogramming vaccine-induced T cells to enhance memory responses in patients with solid tumors following completion of their standard therapy.

We conducted three phase I clinical trials employing New York esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccination approaches, with or without schedule-varied rapamycin. T cell phenotypes, functions, and Vβ usage in peripheral blood were analyzed to ask whether rapamycin influenced the generation of vaccine-induced T cells with memory attributes.

The addition of rapamycin to all vaccination approaches was safe and well tolerated. Immediate (days 1-14 postvaccination) or delayed (days 15-28 postvaccination) administration of rapamycin led to a significant increase in the generation of vaccine-induced NY-ESO-1-specific T cells exhibiting central memory phenotypes (CD45RO+CD45RA- CCR7+). Moreover, delayed administration resulted in a greater than threefold (p=0.025) and eightfold (p=0.005) increase in the frequency of NY-ESO-1-specific CD4+ T and CD8+ T cells respectively at the time of long-term follow-up, compared with its immediate usage.

Our novel finding is that delayed administration of rapamycin to patients during the contraction phase of vaccine-induced antitumor immune responses was particularly effective in increasing the frequency of memory T cells up to 1 year postvaccination in patients with solid tumors. Further studies are warranted to identify the impact of this approach on the durability of clinical remission.

NCT00803569, NCT01536054, NCT01522820.

This review explores the emerging role of T cell exhaustion in allergic diseases and allergen immunotherapy (AIT). It aims to synthesize current knowledge on the mechanisms of T cell exhaustion, evaluate its potential involvement in allergic inflammation, and assess its implications as a novel biomarker for predicting and monitoring AIT efficacy.

Recent studies highlight that T cell exhaustion, characterized by co-expression of inhibitory receptors (e.g., PD-1, CTLA-4, TIM-3), diminished cytokine production, and altered transcriptional profiles, may suppress type 2 inflammation in allergic diseases. In allergic asthma, exhausted CD4 + T cells exhibit upregulated inhibitory receptors, correlating with reduced IgE levels and airway hyperreactivity. During AIT, prolonged high-dose allergen exposure drives allergen-specific Th2 and T follicular helper (Tfh) cell exhaustion, potentially contributing to immune tolerance. Notably, clinical improvements in AIT correlate with depletion of allergen-specific Th2 cells and persistent expression of exhaustion markers (e.g., PD-1, CTLA-4) during maintenance phases. Blockade of inhibitory receptors (e.g., PD-1) enhances T cell activation, underscoring their dual regulatory role in allergy. T cell exhaustion represents a double-edged sword in allergy: it may dampen pathological inflammation in allergic diseases while serving as a mechanism for AIT-induced tolerance. The co-expression of inhibitory receptors on allergen-specific T cells emerges as a promising biomarker for AIT efficacy. Future research should clarify the transcriptional and metabolic drivers of exhaustion in allergy, validate its role across diverse allergic conditions, and optimize strategies to harness T cell exhaustion for durable immune tolerance. These insights could revolutionize therapeutic approaches and biomarker development in allergy management.

Chimeric antigen receptor T cell (CAR-T) therapy has shown success in treating hematological malignancies, but its effectiveness against solid tumors is hindered by T cell exhaustion. During in vitro expansion, tonic signaling induced by CAR expression contributes to CAR-T cell exhaustion, which can be mitigated by inhibiting calcium signaling. Given that sodium citrate can chelate calcium ions and inhibit calcium signaling, in this study, we investigated whether sodium citrate could reduce exhaustion and enhance CAR-T cell function.

We constructed anti-CD70 CAR-T cells and cultured them in the presence of sodium citrate. The characteristics and functionality of sodium citrate-pretreated CAR-T cells were assessed through in vitro and in vivo experiments. To further validate our observation, we also treated anti-mesothelin (MSLN) CAR-T cells with sodium citrate and detected the phenotypes and anti-tumor function of CAR-T cells.

We found that sodium citrate-pretreated anti-CD70 CAR-T cells exhibited reduced exhaustion, increased memory T cell proportions, and enhanced anti-tumor efficacy both in vitro and in vivo. Notably, sodium citrate treatment improved the in vivo persistence of CAR-T cells and prevented tumor recurrence. These beneficial effects were also observed in anti-MSLN CAR-T cells. Transcriptomic and metabolite analyses revealed that sodium citrate inhibited calcium signaling, mTORC1 activity, and glycolysis pathways, thus modulating T cell exhaustion and differentiation.

Our findings suggest that sodium citrate supplementation during CAR-T cell expansion could be a promising strategy to improve CAR-T therapy for solid tumors by preventing exhaustion and promoting memory T cell formation.

Enhancing CART function and persistence while balancing immune effector-mediated inflammation is crucial. Using our clinically relevant HER2-CAR platform, we demonstrate that tumor-intrinsic signals like the PD-1/PD-L1 immune checkpoint can be leveraged in CART design to modulate immune synapse and metabolic parameters, improving antitumor function without increasing cytokine production.

Landmark studies at the turn of the century revealed metabolic reprogramming as a driving force for lymphocyte differentiation and function. In addition to metabolic changes, differentiating lymphocytes must remodel their epigenetic landscape to properly rewire their gene expression. Recent discoveries have shown that metabolic shifts can shape the fate of lymphocytes by altering their epigenetic state, bringing together these two areas of inquiry. The ongoing evolution of high-dimensional cytometry has enabled increasingly comprehensive analyses of metabolic and epigenetic landscapes in lymphocytes that transcend the technical limitations of the past. Here, we review recent insights into the interplay between metabolism and epigenetics in lymphocytes and how its dysregulation can lead to immunological dysfunction and disease. We also discuss the latest technical advances in cytometry that have enabled these discoveries and that we anticipate will advance future work in this area.

The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells. However, the anticancer activity of CD8 T cells and NK cells is rapidly diminished in the tumour microenvironment, closely linked to a decline in their metabolic capacities. Various strategies have been developed to restore cancer immunosurveillance, including targeting bioenergetic metabolism or genetic engineering. This Review provides an overview of metabolic dysfunction in CD8 T cells and NK cells within the tumour microenvironment, highlighting current therapies aiming to overcome these issues.

Autoimmune diseases occur when the immune system abnormally attacks the body's normal tissues, causing inflammation and damage. Each disease has unique immune and metabolic dysfunctions during pathogenesis. In rheumatoid arthritis (RA), immune cells have different metabolic patterns and mitochondrial/lysosomal dysfunctions at different disease stages. In systemic lupus erythematosus (SLE), type I interferon (IFN) causes immune cell metabolic dysregulation, linking activation to metabolic shifts that may worsen the disease. In systemic sclerosis (SSc), mitochondrial changes affect fibroblast metabolism and the immune response. Idiopathic inflammatory myopathies (IIMs) patients have mitochondrial and metabolic issues. In primary Sjögren's syndrome (pSS), immune cell metabolism is imbalanced and mitochondrial damage can lead to cell/tissue damage. Metabolic reprogramming links cellular energy needs and immune dysfunctions, causing inflammation, damage, and symptoms in these diseases. It also affects immune cell functions like differentiation, proliferation, and secretion. This review discusses the potential of targeting metabolic pathways to restore immune balance, offering directions for future autoimmune disease research and treatment.

Lauric acid (LAA) is a 12-carbon medium-chain fatty acid that reportedly has antitumor and muscle-protecting effects. However, the details of these antitumor effects remain unclear. Therefore, in this study, we investigated the mechanism underlying the antitumor effects of LAA in CT26 and HT29 colorectal cancer (CRC) cell lines. Our in vitro findings demonstrated that LAA suppressed CRC cell proliferation, induced mitochondrial oxidative stress (reactive oxygen species (ROS)), inhibited oxidative phosphorylation (OXPHOS), and induced apoptosis. Moreover, in vivo analysis of LAA showed a more pronounced antitumor effect in CT26 cells in a syngeneic mouse tumor model than in vitro; therefore, we further investigated its impact on host antitumor immunity. We observed that LAA increased the number of effector T cells in mouse tumors, while in vitro LAA activated mouse splenocytes (SplC) and promoted OXPHOS. In two-dimensional co-culture of SplC and CT26 cells, LAA induced cell death in cancer cells. In three-dimensional co-culture, LAA promoted SplC infiltration and suppressed the formation of tumor spheres. Thus, LAA may exert antitumor effects through increased ROS production in cancer cells and effector T cell activation via increased energy metabolism. These results suggest that LAA, when used in combination with existing anti-cancer drugs, is likely to exhibit sensitizing effects in terms of both antitumor and antitumor immune effects, and future clinical studies are anticipated.

Chimeric antigen receptor (CAR) T cell therapy shows promise for various diseases. Our studies in humanized mice and nonhuman primates demonstrate that hematopoietic stem cells (HSCs) modified with anti-HIV CAR achieve lifelong engraftment, providing functional antiviral CAR-T cells that reduce viral rebound after antiretroviral therapy (ART) withdrawal. However, T cell exhaustion due to chronic immune activation remains a key obstacle to sustained CAR-T efficacy, necessitating additional measures to achieve functional cure. We recently showed that low-dose rapamycin treatment reduced inflammation and improved anti-HIV T cell function in HIV-infected humanized mice. Here, we report that rapamycin improved CAR-T cell function both in vitro and in vivo. In vitro treatment with rapamycin enhanced CAR-T cell mitochondrial respiration and cytotoxicity. In vivo treatment with low-dose rapamycin in HIV-infected, CAR-HSC mice decreased chronic inflammation, prevented exhaustion of CAR-T cells, and improved CAR-T control of viral replication. RNA-sequencing analysis of CAR-T cells from humanized mice showed that rapamycin downregulated multiple checkpoint inhibitors and upregulated key survival genes. Mice treated with CAR-HSCs and rapamycin had delayed viral rebound after ART and reduced HIV reservoir compared with those treated with CAR-HSCs alone. These findings suggest that HSC-based anti-HIV CAR-T cells combined with rapamycin treatment are a promising approach for treating persistent inflammation and improving immune control of HIV replication.

Metabolic reprogramming is important in primary biliary cholangitis (PBC) development. However, studies investigating the metabolic signature within the liver of PBC patients are limited. In this study, liver biopsies from 31 PBC patients and 15 healthy controls were collected, and comprehensive metabolomics, lipidomics, and proteomics analysis were conducted to characterize the metabolic landscape in PBC. We observed distinct lipidome remodeling in PBC with increased polyunsaturated fatty acid levels and augmented fatty acid β-oxidation (FAO), evidenced by the increased acylcarnitine levels and upregulated expression of proteins involved in FAO. Notably, PBC patients exhibited an increase in glucose-6-phosphate (G6P) and purines, alongside a reduction in pyruvate, suggesting impaired glycolysis and increased purines biosynthesis in PBC. Additionally, the accumulation of bile acids as well as a decrease in branched chain amino acids and aromatic amino acids were observed in PBC liver. We also observed an aberrant upregulation of proteins associated with ductular reaction, apoptosis, and autophagy. In conclusion, our study highlighted substantial metabolic reprogramming in glycolysis, fatty acid metabolism, and purine biosynthesis, coupled with aberrant upregulation of proteins associated with apoptosis and autophagy in PBC patients. Targeting the specific metabolic reprogramming may offer potential targets for the therapeutic intervention of PBC.

Although lipid-derived acetyl-coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3, and RNA sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the Stat1 locus was diminished in ACAT1-/- cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions, and increasing histone acetylation rescued Stat1 expression. Interferon-β release was blunted in ACAT1-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling.

Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8+ T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.

In recent years, immune cell therapy, particularly adoptive cell therapy (ACT), has shown superior therapeutic effects on hematologic malignancies. However, a challenge lies in ensuring that genetically engineered specific T cells maintain lasting anti-tumor effects within the host. The enduring success of ACT therapy hinges on the persistence of memory T (TM) cells, a diverse cell subset crucial for tumor immune response and immune memory upkeep. Notably, TM cell subsets at varying differentiation stages exhibit distinct biological traits and anti-tumor capabilities. Poorly differentiated TM cells are pivotal for favorable clinical outcomes in ACT. The differentiation of TM cells is influenced by multiple factors, including metabolism and cytokines. Consequently, current research focuses on investigating the differentiation patterns of TM cells and enhancing the production of poorly differentiated TM cells with potent anti-tumor properties in vitro, which is a prominent area of interest globally. This review delves into the differentiation features of TM cells, outlining their distribution in patients and their impact on ACT treatment. It comprehensively explores cutting-edge strategies to boost ACT efficacy through TM cell differentiation induction, aiming to unlock the full potential of TM cells in treating hematologic malignancies and offering novel insights for tumor immune cell therapy.

Metformin, the frontline treatment for diabetes, has considerable potential as an immunomodulator; however, detailed bibliometric analyses on this subject are limited.

This study extracted 640 relevant articles from the Web of Science (WOS) Core Collection and conducted visual analyses using Microsoft Excel, VOSviewer, and CiteSpace.

The findings showed that research on the immunomodulatory function of metformin has grown steadily since 2017, with China and the United States being the leading contributors. These studies have mostly been published in journals such as the International Journal of Molecular Sciences, Cancers, Frontiers in Immunology, and Scientific Reports. Keyword co-occurrence analysis highlighted metformin's role as an immunomodulator, particularly in the context of the tumor immune microenvironment, immunosuppressive checkpoints, and metformin derivatives. Recent research has highlighted metformin's application in aging, autoimmune diseases, COVID-19, and tuberculosis. Additionally, its role in regulating inflammation and gut microbiota is also being investigated.

Overall, the immunomodulatory effects of metformin were investigated in anti-tumor, antiviral, anti-aging, and autoimmune disease research. This highlights the scope of metformin use in these fields, while also significantly enhancing its clinical value as a repurposed drug.

Immunotherapy has transformed current cancer management, and it has achieved significant progress over last decades. However, an immunosuppressive tumor microenvironment (TME) diminishes the effectiveness of immunotherapy by suppressing the activity of immune cells and facilitating tumor immune-evasion. Adenosine monophosphate-activated protein kinase (AMPK), a key modulator of cellular energy metabolism and homeostasis, has gained growing attention in anti-tumor immunity. Metformin is usually considered as a cornerstone in diabetes management, and its role in activating the AMPK pathway has also been extensively explored in cancer therapy although the findings on its role remain inconsistent. Metformin in a nanomedicine formulation has been found to hold potential in reprogramming the immunosuppressive TME through immunometabolic modulation of both tumor and immune cells. This review elaborates the foundation and progress of immunometabolic reprogramming of the TME via metformin-based nanomedicines, offering valuable insights for the next generation of cancer therapy.

Chronic kidney disease (CKD), defined as persistent (>3 months) kidney functional loss, has a growing prevalence (>10% worldwide population) and limited treatment options. Fibrosis driven by the aberrant accumulation of extracellular matrix is the final common pathway of nearly all types of chronic repetitive injury in the kidney and is considered a hallmark of CKD. Myofibroblasts are key extracellular matrix-producing cells that are activated by crosstalk between damaged tubules and immune cells. Emerging evidence indicates that metabolic alterations are crucial contributors to the pathogenesis of kidney fibrosis by affecting cellular bioenergetics and metabolite signalling. Immune cell functions are intricately connected to their metabolic characteristics, and kidney cells seem to undergo cell-type-specific metabolic shifts in response to damage, all of which can determine injury and repair responses in CKD. A detailed understanding of the heterogeneity in metabolic reprogramming of different kidney cellular subsets is essential to elucidating communication processes between cell types and to enabling the development of metabolism-based innovative therapeutic strategies against CKD.

Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct species differentially modulating CD8+ T cell (CTL) fate and function. Indeed, lipids can influence T cell signaling by altering their membrane composition; in addition, they can affect the differentiation path of T cells through cellular metabolism. This Review discusses the ability of lipids to shape T cell phenotypes and functions. Based on this link between lipid metabolism, metabolic fitness and immunosurveillance, we suggest that lipid could be rationally integrated in the context of immunotherapies to fine-tune fitness and function of adoptive T cell therapy (ACT) products.

Immunosenescence, the age-related decline in immune function, is a complex biological process with profound implications for health and longevity. This phenomenon, characterized by alterations in both innate and adaptive immunity, increases susceptibility to infections, reduces vaccine efficacy, and contributes to the development of age-related diseases. At the cellular level, immunosenescence manifests as decreased production of naive T and B cells, accumulation of memory and senescent cells, thymic involution, and dysregulated cytokine production. Recent advances in molecular biology have shed light on the underlying mechanisms of immunosenescence, including telomere attrition, epigenetic alterations, mitochondrial dysfunction, and changes in key signaling pathways such as NF-κB and mTOR. These molecular changes lead to functional impairments in various immune cell types, altering their proliferative capacity, differentiation, and effector functions. Emerging research suggests that lifestyle factors may modulate the rate and extent of immunosenescence at both cellular and molecular levels. Physical activity, nutrition, stress management, and sleep patterns have been shown to influence immune cell function, inflammatory markers, and oxidative stress in older adults. This review provides a comprehensive analysis of the molecular and cellular mechanisms underlying immunosenescence and explores how lifestyle interventions may impact these processes. We will examine the current understanding of immunosenescence at the genomic, epigenomic, and proteomic levels, and discuss how various lifestyle factors can potentially mitigate or partially reverse aspects of immune aging. By integrating recent findings from immunology, gerontology, and molecular biology, we aim to elucidate the intricate interplay between lifestyle and immune aging at the molecular level, potentially informing future strategies for maintaining immune competence in aging populations.

The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.

Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Understanding the metabolic diversities among cancer cells and their surrounding environments is therefore essential in unravelling the complexities of leukaemia and improving therapeutic strategies. Here, we describe the currently available methodologies and approaches to addressing the dynamic heterogeneity of leukaemia progression. In the second section, we focus on metabolic leukaemic vulnerabilities in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Lastly, we provide a comprehensive overview of the most interesting clinical trials designed to target these metabolic dependencies, highlighting their potential to advance therapeutic strategies in leukaemia treatment. The integration of multi-omics data for cancer identification with the metabolic states of tumour cells will enable a comprehensive "micro-to-macro" approach for the refinement of clinical practices and delivery of personalised therapies.

We have shown that virus-specific CD4 and CD8 memory T cells (TM) induce autophagy after T cell receptor (TCR) engagement to provide free glutamine and fatty acids, including in people living with HIV-1 (PLWH). These nutrients fuel mitochondrial ATP generation through glutaminolysis and fatty acid oxidation (FAO) pathways, to fulfill the bioenergetic demands for optimal IL-21 and cytotoxic molecule production in CD4 and CD8 cells, respectively. Here, we expand our knowledge on how the metabolic events that occur in the mitochondria of virus-specific TM down-stream of the autophagy are regulated. We show that HSP60 chaperone positively regulates the protein levels for multiple glutaminolysis- and FAO-related enzymes, thereby actively fueling the levels of cellular alpha-ketoglutarate (αKG) and related mitochondrial ATP-dependent antiviral T cell immunity in both CD4 and CD8 TM. Finally, we provide a way to rescue defective ATP generation in mitochondria and dependent effector functions in virus-specific TM including anti-HIV-1 protective responses, when HSP60 expression is impaired after TCR engagement in patients, in the form of dimethyl 2-oxoglutarate (DMKG) supplementation.

Many cancer immunotherapies rely on robust CD8+ T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8+ tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation. Targeting metabolism holds promise for enhancing CD8+ T cell-mediated antitumor immunity. Here, we overview the metabolic features of CD8+ TILs and their impact on T cell effector function and differentiation. We also highlight immunoengineering strategies by leveraging the Yin-Yang of metabolic modulation for improving cancer immunotherapy.

T cell Antigen Coupler (TAC) T cells harness all signaling subunits of endogenous T cell receptor (TCR) to trigger T-cell activation and tumor cell lysis, with minimal release of cytokines. Some of the major obstacles to cellular immunotherapy in solid tumors include inefficient cell infiltration into tumors, lack of prolonged cellular persistence, and therapy-associated toxicity.

To boost the cytotoxic potential of TAC-T cells against solid tumors, we generated a novel NECTIN-4-targeted TAC-T variant, NECTIN-4 TAC28-T, which integrated the co-stimulatory CD28 cytoplasmic region, and compared the anti-tumor activities between NECTIN-4 TAC-T cells and NECTIN-4 TAC28-T cells in vitro and vivo.

We demonstrated NECTIN-4 TAC28-Tcells could be effectively activated by NECTIN-4 protein-coated magnetic beads (NECTIN-4-beads), and further revealed that the incorporated CD28 co-stimulatory domain enhanced their activation and proliferation capabilities. Notably, NECTIN-4 TAC28-T cells exhibited better anti-tumor effects both in vitro and in vivo than the original NECTIN-4 TAC-T cells.

Our data highlighted that NECTIN-4 TAC28-T cells may represent a promising, safe and effective cell therapy for NECTIN-4-overexpressing solid tumors.

Peroxisomes are increasingly linked to cancer development, yet the prognostic role of peroxisome-related genes (PRGs) in breast cancer remains unclear.

This study aimed to construct a prognostic model based on PRG expression in breast cancer to clarify their prognostic value and clinical implications.

Transcriptomic data from TCGA and GEO were used for training and validation cohorts. TME characteristics were analyzed with ESTIMATE, MCP-counter, and CIBERSORT algorithms. qPCR validated mRNA expression levels of risk genes, and data analysis was conducted in R.

Univariate and multivariate Cox regression identified a 7-gene PRG risk signature (ACBD5, ACSL5, DAO, NOS2, PEX3, PEX10, and SLC27A2) predicting breast cancer prognosis in training (n=1069), internal validation (n=327), and external validation (merged from four GEO datasets, n=640) datasets. While basal and Her2 subtypes had higher risk scores than luminal subtypes, a significant prognostic impact of the PRG risk signature was seen only in luminal subtypes. The high-risk subgroup exhibited a higher frequency of focal synonymous copy number alterations (SCNAs), arm-level amplifications and deletions, and single nucleotide variations. These increased genomic aberrations were associated with greater immune suppression and reduced CD8+ T cell infiltration. Bulk RNA sequencing and single-cell analyses revealed distinct expression patterns of peroxisome-related genes (PRGs) in the breast cancer TME: PEX3 was primarily expressed in malignant and stromal cells, while ACSL5 showed high expression in T cells. Additionally, the PRG risk signature demonstrated efficacy comparable to that of well-known biomarkers for predicting immunotherapy responses. Drug sensitivity analysis revealed that the PRG high-risk subgroup was sensitive to inhibitors of BCL-2 family proteins (BCL-2, BCL-XL, and MCL1) and other kinases (PLK1, PLK1, BTK, CHDK1, and EGFR).

The PRG risk signature serves as a promising biomarker for evaluating peroxisomal activity, prognosis, and responsiveness to immunotherapy in breast cancer.

Fatty acids play critical roles in maintaining the cellular functions of T cells and regulating T-cell immunity. This review synthesizes current research on the influence of fatty acids on T-cell subsets, including CD8+ T cells, TH1, TH17, Treg (regulatory T cells), and TFH (T follicular helper) cells. Fatty acids impact T cells by modulating signaling pathways, inducing metabolic changes, altering cellular structures, and regulating gene expression epigenetically. These processes affect T-cell activation, differentiation, and function, with implications for diseases such as autoimmune disease and cancer. Based on these insights, fatty acid pathways can potentially be modulated by novel therapeutics, paving the way for novel treatment approaches for immune-mediated disorders and cancer immunotherapy.