Metabolic Reprogramming in Immune Cells: Complex Regulation of the Functions in Innate and Adaptive Immunity

Metabolic Reprogramming in Immune Cells: Complex Regulation of the Functions in Innate and Adaptive Immunity | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 30 July 2025 V1 Latest version Share on Metabolic Reprogramming in Immune Cells: Complex Regulation of the Functions in Innate and Adaptive Immunity Authors : Guoshuai Tong , Jingwen Dai , Qianqian Liu , Xu Gao , Su Li 0000-0002-5845-4617 , and Hua-Ji Qiu [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175388092.20407383/v1 424 views 222 downloads Contents Abstract 2.3. Molecular mechanisms of immunotherapy strategies mediated by metabolic reprogramming Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Summary: Metabolic reprogramming dynamically regulates antiviral defense across innate and adaptive immunity. Immune cells exert their antiviral functions by undergoing metabolic reprogramming. In this review, the significance of metabolic reprogramming of immune cells is discussed, including the effects of metabolic pathways, such as glycolysis, oxidative phosphorylation (OXPHOS), tricarboxylic acid (TCA) cycle, pentose phosphate pathway (PPP), and fatty acid oxidation (FAO) on the maturation, differentiation and function of immune cells. Furthermore, this review elaborates on the specific effects of metabolic reprogramming on various immune cell types, including T cells, B cells, macrophages and dendritic cells (DCs). It covers the metabolic changes following T cell activation and subpopulation differentiation, B cell metabolic remodeling in germinal center response, and macrophage polarization and dendritic cell immunogenicity and immune tolerance. This review summarizes the recent advance of metabolic reprogramming on the effects of the direct regulation of immunotherapy strategies, proinflammatory response, adaptive immunity, as well as the indirect regulation of adaptive immunity through innate immunity. It is worth noting that this review proposes immunotherapy strategies targeting metabolic pathways and the application of metabolic modulators in immunotherapy, and analyzes the key role of metabolic reprogramming in adaptive immune regulation, emphasizing its potential application in the treatment of inflammatory diseases. Metabolic Reprogramming in Immune Cells: Complex Regulation of the Functions in Innate and Adaptive Immunity Guoshuai Tong a, b, c , Jingwen Dai a, c , Qianqian Liu a, b , Xu Gao b * , Su Li a * , and Hua-Ji Qiu a * a State Key Laboratory for Animal Disease Control and Prevention, National African Swine Fever Para-Reference Laboratory, National High Containment Facilities for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China; b Agricultural College, Yanbian University, Yanji, China. c These authors contributed equally to this work. * Correspondence at: Hua-Ji Qiu, PhD Su Li, PhD Xu Gao PhD State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, CAAS 678 Haping Road Harbin 150069 Heilongjiang, China Phone and fax: +86-451-51051708 Email: [email protected] (H.-J.Q.); [email protected] (S.L.); [email protected] (X.G.). Summary: Metabolic reprogramming dynamically regulates antiviral defense across innate and adaptive immunity. Immune cells exert their antiviral functions by undergoing metabolic reprogramming. In this review, the significance of metabolic reprogramming of immune cells is discussed, including the effects of metabolic pathways, such as glycolysis, oxidative phosphorylation (OXPHOS), tricarboxylic acid (TCA) cycle, pentose phosphate pathway (PPP), and fatty acid oxidation (FAO) on the maturation, differentiation and function of immune cells. Furthermore, this review elaborates on the specific effects of metabolic reprogramming on various immune cell types, including T cells, B cells, macrophages and dendritic cells (DCs). It covers the metabolic changes following T cell activation and subpopulation differentiation, B cell metabolic remodeling in germinal center response, and macrophage polarization and dendritic cell immunogenicity and immune tolerance. This review summarizes the recent advance of metabolic reprogramming on the effects of the direct regulation of immunotherapy strategies, proinflammatory response, adaptive immunity, as well as the indirect regulation of adaptive immunity through innate immunity. It is worth noting that this review proposes immunotherapy strategies targeting metabolic pathways and the application of metabolic modulators in immunotherapy, and analyzes the key role of metabolic reprogramming in adaptive immune regulation, emphasizing its potential application in the treatment of inflammatory diseases. Keywords: Metabolic reprogramming; Innate immunity; Adaptive immunity; Immune regulation; Immunotherapy 1. Introduction Metabolic reprogramming allows immune cells to adapt to environmental cues, critically governing their maturation, differentiation, and effector functions. Metabolic reprogramming encompasses five metabolic pathways, which produce ATP, NADPH, pyruvic acid, and acetyl-CoA to facilitate the rapid proliferation, effector function, and anti-inflammatory response of immune cells (Codo et al., 2020; Gao et al., 2019; Pearce and Pearce, 2013). The innate immune system serves as the first line of defense, including physical and chemical barriers, cellular components [such as macrophages, DCs, natural killer (NK) cells], and soluble mediators [complement system and cytokines] (Figure 1). It activates inflammation and participates in antigen presentation, linking to adaptive immunity, triggering proinflammatory cytokines and taking part in antigen presentation (Xia et al., 2025; Jiang et al., 2023; Ruhland et al., 2020). Adaptive immunity consists of two major types of lymphocytes, T cells, and B cells, which recognize and respond to specific non-autoantigens (Figure 1). Both perform the functions of eliminating pathogens, generating immune memory, and providing long-term protection (Xiao et al., 2021; Shepherd and McLaren, 2020). Furthermore, various T cells, including effector type 1 helper T (Th1), Th2, Th17, and regulatory T cells (Tregs), exhibit distinct metabolic profiles (Figure 1). The interplay between innate immunity and adaptive immunity engages in signal transduction, cytokine stimulation, antigen presentation, and immune memory formation, revealing significant implications for the treatment of immune-related diseases and cancers. By precisely regulating the interaction between these two immune systems, pathogens and diseases can be combated more effectively. Metabolic reprogramming not only alters the functions of individual immune cells but also coordinates the interactions between innate immunity and adaptive immunity, thereby modulating the efficacy of immune responses. 2. Relationship between metabolic reprogramming and adaptive immunity 2.1. The metabolic reprogramming in the complex regulation of T and B cells Generally, T cells and B cells exhibit low metabolic activity, primarily relying on mitochondrial OXPHOS for energy production in the resting state. The resting T cells sustain basal functions via the oxidative metabolism of glucose and glutamine. Transcription factors, such as paired box protein 5 (Pax5) and IKZF1, suppress glucose uptake and ribonucleotide synthesis, maintaining a quiescent metabolic state (Martinis et al., 2025; Chan et al., 2017; Simula et al., 2024) (Figure 2). Upon activation of T cells, the metabolic pathways undergo substantial reprogramming. Rely on the Warburg effect to support rapid proliferation and effector functions. This is triggered by TCR signals and costimulatory signals, increasing glucose uptake and glycolysis rate by up-regulating the glucose transporter Glut1 and mechanistic target of rapamycin (mTOR) signaling pathways. The mTOR signaling pathway integrates TCR and costimulatory signals in T cell metabolic reprogramming, activates downstream transcription factors c-Myc and HIF-1α, promotes the expression of glycolysis-related genes, and also supports cell growth and proliferation through glutamine metabolism and fatty acid synthesis (Jin et al., 2023; Martinis et al., 2025; Shyer et al., 2020; Wang et al., 2019; Yoo et al., 2020) (Figure 2). In contrast, activated B cells exhibit different characteristics in metabolism. Although B cells also rely on glycolysis to support proliferation, they prefer to maintain high levels of mitochondrial OXPHOS to support antibody glycosylation and mitochondrial oxidation of fatty acids (Akkaya and Pierce, 2019). This metabolic pattern might be associated with the differentiation of B cells into antibody-secreting plasma cells. In the germinal center, B cells undergo multiple rounds of hypermutation, proliferation and positive selection, requiring a large amount of energy and biosynthetic capabilities to support antibody synthesis and secretion. Therefore, maintaining a high level of OXPHOS can provide a stable energy supply and biosynthetic precursors, and its metabolism is regulated by multiple signaling pathways and transcription factors such as BAFF and its receptor BAFF-R (Gracie et al., 2025; Li et al., 2023). Taken together, both T cells and B cells rely on mitochondrial oxidative metabolism at resting state, however, upon activation, T cells tend to aerobic glycolysis, while B cells maintain high OXPHOS levels to meet their respective functional requirements (Figure 2). 2.2. Effects of metabolic reprogramming on the differentiation of T cell subsets Metabolic reprogramming plays a crucial role in the differentiation of Th1, Th2, Th17, and Treg cells. The differentiation and functional execution of these T cell subsets are closely related to specific metabolic pathways. Glycolysis and mTOR pathways are activated to enhance antiviral activities in Th1 cells (Kolland et al., 2025; Nour et al., 2025; Johnson et al., 2018; Klysz et al., 2015). Th2 cells are predominantly activated by IL-4, GATA3 of Th2 is activated. GATA3 can inhibit the expression of glycolysis related genes and promote the expression of OXPHOS related genes simultaneously (Callender et al., 2021; Ouyang et al., 2000; Seki et al., 2004). Impaired Th17 function is associated with abnormal glycolysis and inhibition of glutaminase, while the decreased stability of Treg may result from the dysregulation of OXPHOS or FAO (Johnson et al., 2018; Kempkes et al., 2019; Kono et al., 2019; Shin et al., 2020; Wu et al., 2020). Virus infection results in the change of the direction and intensity of the immune response by directly inhibiting metabolic enzymes, inducing hypoxia or destroying mitochondrial function, altering metabolic pathways and driving imbalances in T cell subsets (Figure 3). Collectively, metabolic reprogramming significantly influences the differentiation and functions of Th1, Th2, and Th17 cells and Tregs through modulating various metabolic pathways. By altering epigenetic regulation and signaling pathways, modifications to these metabolic processes may also regulate the development of T cell subsets in addition to impacting the cells’ energy supply. 2.3. Molecular mechanisms of immunotherapy strategies mediated by metabolic reprogramming Immune cell metabolic reprogramming is closely related to immunotherapy resistance. One of the mechanisms of immunotherapy resistance is the functional disorder caused by the abnormal metabolism of immune cells. Under normal circumstances, immune cells rely on metabolic pathways such as glycolysis and OXPHOS to generate energy and biosynthetic precursors to maintain their normal functions. However, under pathological conditions such as viral infections, immune cells may be affected by multiple factors, leading to metabolic disorders. For instance, in COVID-19 infection, abnormal mitochondrial regulation of B cells can affect their acute response to the severity of the disease and thereby may influence the efficacy of immunotherapy (Codo et al., 2020; Lee et al., 2022; Zhu et al., 2025; Mullen et al., 2021). Furthermore, the metabolic reprogramming of immune cells may also be regulated by other cells or molecules, such as extracellular matrix components, etc., which can affect the efficacy of immunotherapy by influencing the metabolic state of immune cells (O’Neill and Pearce, 2015; Sutherland et al., 2023). Regarding the relationship between immune cell metabolic reprogramming and immunotherapy resistance, existing studies have shown that regulating immune cell metabolism can overcome resistance. For example, inhibiting glycolysis can improve the effect of immunotherapy by regulating the metabolic state of immune cells. Meanwhile, intervening in the key enzymes or signaling pathways of immune cell metabolism, such as inhibiting the mTOR signaling pathway, can improve the function of immune cells and enhance the efficacy of immunotherapy (Tang et al., 2024; Thomson et al., 2009; Panwar et al., 2023; Inamdar et al., 2023). Furthermore, the combined use of immunotherapy and metabolic regulatory drugs is also an effective strategy. By simultaneously regulating the metabolism and function of immune cells, the therapeutic effect of immunotherapy on drug-resistant diseases can be enhanced (Su et al., 2024). In conclusion, immune cell metabolic reprogramming plays a significant role in the emergence and development of immunotherapy resistance. In-depth research on its mechanism and intervention strategies is of great significance for improving the efficacy of immunotherapy. 2.4. Metabolic reprogramming induced in viral infections regulates adaptive immunity Viruses precisely regulate adaptive immunity through metabolic reprogramming. For instance, PRRSV infection upregulates lipid droplet synthesis through the transcription factor YY1 and limits the free fatty acids to facilitate viral replication. Meanwhile, the virus activates endoplasmic reticulum stress (ERs) by degrading the GRP78 protein and hijacks activating transcription factor 4 (ATF4) and X-box binding protein 1 (XBP1s) to promote viral RNA synthesis. This dual strategy not only inhibits the virus release but also interferes with the recognition of infected cells by CD8+ T cells (Zheng et al., 2024; Gao et al., 2019; Cai et al., 2023; Chathuranga et al., 2021) (Table 1). Furthermore, PEDV hijacks the ESCRT complex for virus budding and utilizes the cellular TSG101 protein to interfere with energy metabolism. This metabolic reprogramming inhibits T cell activation and reduces the efficiency of neutralizing antibodies (Chen et al., 2024; Vardhana et al., 2010) (Table 1). IAV generates fumaric acid through the aspartate argininosuccinate (AAS) bypass driven by ASS1. The latter enhances the retinoid acid-inducible gene I (RIG-I) signaling pathway by amber acidifying mitochondrial antiviral signaling (MAVS) protein and promotes the interferon β (IFN-β) production. This mechanism not only enhances innate immunity but also activates CD8+ T cells through the cross-presentation of dendritic cells, forming a positive feedback of adaptive immunity (Xia et al., 2025; Jiang et al., 2023; Rashid et al., 2023) (Table 1). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diverts host tryptophan metabolism toward the kynurenine pathway, thereby activating the aryl hydrocarbon receptor (AHR) pathway and consequently suppressing the function of regulatory T cells (Tregs) (Xiao et al., 2021) (Table 1). Future research needs to focus on the spatiotemporal dynamic characteristics of the metabolism-immune interaction network and develop combined therapies targeting key nodes (such as YY1, ASS1, and AhR) to restore immune homeostasis and block immune escape. Metabolic reprogramming has a significant impact on immune function. Innate immune cells, as the primary response of pathogens and the coordinators of adaptive immune activation, their interaction is influenced by shared metabolic pathways. Viral infection can reshape the metabolism of T cells, B cells and innate immune cells, forming a bidirectional regulatory network. Metabolic crosstalk is conducive to the initiation of adaptive immunity by the innate immune system and is regulated by its feedback. Understanding this metabolism-immune axis is of great significance for revealing the strategies by which pathogens utilize cellular metabolism and restore immune homeostasis. The following text will deeply explore the mechanism of innate immune metabolic reprogramming and its role in bridging immune responses. 3. The interaction between metabolic reprogramming and innate immunity 3.1. Engagement of metabolic reprogramming in macrophages and DCs M1-type macrophages can facilitate the proliferation and differentiation of T cells, promote the polarization of Th1 cells, and enhance cellular immune responses by secreting a large number of proinflammatory cytokines, such as IL-1β, TNF-α, etc. Meanwhile, M1-type macrophages can also attract T cells to the infection site through antigen presentation and secretion of chemokines, and participate in the immune response. M2-type macrophages play an important role in maintaining immune balance and tissue repair by secreting anti-inflammatory cytokines such as IL-10, inhibiting the activation of Th1 cells, promoting the differentiation of Th2 cells, and inducing immune tolerance (Aa, 2023; Chuang et al., 2016; Yu et al., 2022) (Figure 4). DCs are the critical cells that initiate adaptive immunity, and they affect the adaptive immune response through multiple aspects such as antigen presentation and secretion of cytokines. Upon the uptake of antigens by immature DCs, they underscore the maturation and migration to lymphoid organs under specific stimulus signals, presenting antigen to T cells, activating primary T cells and enabling their proliferation and differentiation into effector T cells, including cytotoxic T cells and helper T cells, thereby initiating a specific immune response (Del Prete et al., 2023) (Figure 4). The costimulatory molecules of mature DCs bind to the receptors on the surface of T cells, providing the necessary second signal for T cell activation and enhancing the activation of T cells and the intensity of immune responses (Hubo et al., 2013). In addition, cytokines secreted by DCs, such as IL-12, can regulate the balance of Th1/Th2 cells, promote the differentiation of Th1 cells, and enhance the cellular immune response. Moreover, certain subsets of DCs can also induce the production of regulatory T cells (Treg), playing a key role in maintaining immune tolerance and autoimmune regulation (Zou et al., 2010; Christensen et al., 2002). 3.2. Crosstalk between metabolic reprogramming and proinflammatory response Metabolic reprogramming indirectly affects adaptive immunity by regulating inflammatory responses. Upon activation, macrophages and DCs undergo metabolic reprogramming that shifts from OXPHOS to glycolytic metabolism (Sun et al., 2020). This metabolic transformation not only provides energy for cells but also promotes the accumulation of multiple metabolic intermediates, which play an important role in immune regulation. For instance, fumarate accumulation in macrophages is associated with mitochondrial stress and IFN-β release, a process that requires the involvement of receptors, such as TLR7, DDX58, and IFIH14 (Jeridi et al., 2023). During the proinflammatory response, metabolic intermediates, including succinic and fumaric acids, regulate immune cell activation and cytokine production, affecting both innate and adaptive immune cells, such as T cells. Specifically, succinic acid promotes the production of IL-1β through the HIF-1α pathway, thereby enhancing the proinflammatory response (Wu et al., 2023). In addition, metabolic reprogramming also affects the maturation and functions of DCs. Upon activation, DCs increase glycolytic metabolism to support their functions of antigen presentation and T cell activation. This metabolic transformation facilitates DCs to better exert their immunogenicity in the inflammatory microenvironment, thereby activating adaptive immune responses. Maintaining high levels of mitochondrial oxidative phosphorylation is associated with DC tolerance and helps prevent excessive immune responses (X. Zhang et al., 2024). Metabolic reprogramming indirectly influences the activation and regulation of adaptive immunity through modulating metabolic intermediates and cellular metabolic pathways in the proinflammatory response, a process that not only plays a key role in inflammatory diseases but also provides potential targets for the development of new therapeutic strategies (Sun et al., 2020; Zhang et al., 2024). 3.3. Metabolic reprogramming and immune memory Immune memory refers to the ability of the immune system to remember an antigen for a long time after its first exposure and to generate an immune response quickly and efficiently upon re-exposure. This process involves a variety of immune cells, including DCs, macrophages, etc., and metabolic reprogramming plays a key role in this process. Macrophage metabolic polarization shapes the immune memory microenvironment. M1-type macrophages rely on glycolysis and succinate dehydrogenase (SDH) to produce proinflammatory factors, while M2-type macrophages support tissue repair through OXPHOS and the urea cycle. Succinic acid accumulation prolongs inflammatory memory by stabilizing HIF-1α, while itaconic acid promotes the tolerance phenotype by inhibiting SDH (Wu et al., 2024; Mills and O’Neill, 2016; Tannahill et al., 2013; Rőszer, 2015). Cholesterol metabolism reprogramming affects the long-term residence of macrophages in tissues by regulating LXR signals, and its abnormalities can lead to immune memory disorders (Clark et al., 2025; Feehan et al., 2024). This bidirectional metabolic regulatory mechanism makes macrophages the key shapers of the immune memory microenvironment. Lipid metabolism in DCs regulates antigen-presenting efficacy. DCs support the synthesis of MHC-II molecules and cell migration through glycolytic burst, while the activation of lipid synthase ACC1 can inhibit the secretion of IL-12 (Liu et al., 2021; Guak et al., 2018). Mitochondrial reactive oxygen species (mtROS) enhance the cross-presentation ability by stabilizing HIF-1α, but excessive ROS can induce apoptosis (Ersching et al., 2017). Recently, DCs have been shown to maintain the activation of memory T cells through the uptake of exogenous fatty acids, and its metabolite itaconic acid can inhibit proinflammatory responses. This metabolic plasticity enables DCs to both initiate a robust immune response and prevent excessive inflammatory damage. 3.4. Viral infection induces metabolic reprogramming to innate-adaptive immunity interplay and redox regulation in immune response Viruses construct ”metabolism-immune Bridges” through metabolic reprogramming and indirectly regulate adaptive immunity with innate immunity as the hub. ASFV infection significantly upregulates the intermediate products of TCA, such as citric acid and α-ketoglutaric acid (AKG) and simultaneously increases the levels of aspartic acid and glutamic acid in porcine alveolar macrophages, providing precursor substances for viral genomic replication. Furthermore, ASFV inhibits the RIG-I signaling pathway through lactate dehydrogenase (LDH) -mediated lactate accumulation, and reduces IFN-β production, thereby antagonizing the antiviral activity of NK cells and CD8+ T cells (Table 2). PCV2 infection inhibits the production of CPT1A, a key enzyme for fatty acid oxidation, leading to the accumulation of mitochondrial reactive oxygen species (ROS) and abnormal activation of NLRP3 inflammasomes in porcine monocytes. Meanwhile, the virus inhibits the secretion of IL-1β through the PPARα pathway, hindering the differentiation of Th1 cells (Zheng et al., 2024). DENV utilizes host lipid droplets as a viral particle assembly platform, causing macrophages to release a large amount of inflammatory factors (such as IL-6 and TNF-α). Although this ”inflammatory storm” temporarily enhances the level of neutralizing antibodies, it intensifies T cell apoptosis and eventually leads to immunopathological damage (Chatel-Chaix et al., 2010; Onomoto et al., 2021) (Table 2). HCV infection results in the cleavage of the MAVS protein through NS3/4A to block the IFN signaling, while disrupting cholesterol metabolism and inhibiting the maturation of DCs. DCs with metabolic disorders highly express PD-L1, inducing the exhaustion of virus-specific CD8+ T cells and resulting in chronic infections (Chatel-Chaix et al., 2010; Osuch et al., 2020) (Table 2). Additionally, ASFV regulates host energy metabolism and immune responses through differentiated strategies, providing novel insights into the development of broad-spectrum antiviral therapies targeting ”metabolic checkpoints”. Future studies need to further analyze the virus-host metabolic interaction network and explore cross-species conserved regulatory mechanisms. 4. Metabolic intervention strategies 4.1. Immunotherapy strategies targeting metabolic pathways Inhibition of glycolysis can reduce the energy supply and lactic acid production of tumor cells. For example, 2-deoxyglucose (2-DG) enhances T cell activity by restricting glycolysis (M et al., 2013). Regulating glutamine metabolism can target the amino acid metabolism dependent on tumor cell proliferation and alleviate the nutritional competition of T cells at the same time. For example, glutaminase inhibitors enhance the anti-tumor immune response by balancing substrate distribution. Regulation of lipid metabolism (such as inhibiting fatty acid synthase FASN) can suppress the proliferation of tumor cells and maintain the mitochondrial function of T cells, and the subsequently activated OXPHOS [such as using dichloroacetic acid (DCA)] can enhance the metabolic adaptability of T cells, thereby synergically improving the immune microenvironment to promote the anti-tumor activity and memory formation (Yu et al., 2021). The research team led by Jiang Peng from Tsinghua University has discovered that in the early stage of viral infection, by activating the urea cycle and the tricarboxylic acid (TCA) cycle in macrophages to reprogram in a coordinated manner, the AAS bypass is formed, promoting the production of fumaric acid. Fumaric acid activates the RIG-I receptor pathway through mitochondrial antiviral signaling protein (MAVS) amber acidification and enhances the expression of IFN-β, thereby improving the antiviral innate immune response (Xia et al., 2025). This mechanism reveals the key role of metabolic reprogramming in antiviral immunity and provides a new strategy for targeted metabolic intervention. 4.2. Applications of metabolic modulators in immunotherapy As an adjunct to immunotherapy, metabolic modulators can enhance the efficacy of immunotherapy by modulating metabolic pathways in TME. Reportedly, the metabolic reprogramming of tumor cells can affect the function of immune cells, thus affecting the effect of immunotherapy, For example, by inhibiting immunosuppressive metabolic pathways, such as CD36-dependent FAO, the metabolic requirements of immunosuppressive cells can be reduced, thereby enhancing the anti-tumor activity of immune cells (Huang et al., 2025). In addition, by regulating metabolic pathways of immune cells, such as enhancing glutamine metabolism, the differentiation of Th17 and Th1 cells can be promoted, which is essential for immune response. Other studies have pointed out that metabolic regulators can regulate the expression of immune checkpoint molecules, such as PD-L1, thereby affecting the activity of immune cells. These findings indicate that metabolic regulators indirectly affect the effects of immunotherapy by modulating the metabolic pathways of immune cells, providing a new strategy for cancer treatment. Thus, by boosting TME and modifying immune cell activation, modulators that target metabolic pathways can be a potent adjunct to immunotherapy, increasing therapeutic efficacy. 5. Conclusions and outlooks Metabolic reprogramming plays a key role in the regulation of immune cell function. Various studies have shown that metabolic reprogramming affects the maturation, differentiation and function of immune cells, and changes in metabolic pathways such as glycolysis, OXPHOS and TCA cycle have significant effects on immune cell function (Cao et al., 2023). Metabolic reprogramming functions distinctly in various immune cells, including T cells, B cells, macrophages and DCs. Moreover, metabolic reprogramming is intricately associated with immunotherapy resistance, immunoinflammatory response, and immune memory formation. Metabolic reprogramming induced by viral infection affects adaptive immunity both directly and indirectly through innate immunity (Zhang et al., 2024). The current research has limitations in the analysis of model physiological correlations and metabolic regulatory networks: Existing in vitro or animal models have difficulties in restoring the heterogeneity of the human immune microenvironment and dynamic metabolic interactions. It is necessary to integrate patient organoids-immune co-culture, single-cell multi-omics (spatial metabolomics, ATAC-seq), and microfluidic chip platforms. Meanwhile, the synergistic mechanism of the metabolic-epigenetic-signaling pathway has not yet been clarified. It is necessary to systematically analyze the dynamic regulatory networks (such as the AMPK-mTOR-acetylation axis) through metabolic flux analysis learning modeling, CRISPR-Cas9-mediated gene perturbation and time-resolved metabolic tracking (isotope tracing). Ultimately, organ-on-a-chip was used to verify the spatio-temporal specificity of the target and guide the personalized immunotherapy strategy. Conflict of interest The author declares no conflict of interest. Acknowledgements This work was supported by the National Natural Science Foundation of China [grant no. 32473002] and the Heilongjiang Provincial Natural Science Foundation of China [grant no. TD2023C007]. References Aa, B., 2023. The kynurenine pathway of tryptophan metabolism: a neglected therapeutic target of COVID-19 pathophysiology and immunotherapy. Biosci. Rep. 43. https://doi.org/10.1042/BSR20230595Akkaya, M., Pierce, S.K., 2019. From zero to sixty and back to zero again: the metabolic life of B cells. Curr. Opin. Immunol. 57, 1–7. https://doi.org/10.1016/j.coi.2018.09.019Cai, H., Zhang, H., Cheng, H., Liu, M., Wen, S., Ren, J., 2023. Progress in PRRSV infection and adaptive immune response mechanisms. 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Metabolic regulation mechanisms of innate and adaptive immune responses in the immune system. Danger signals activate the metabolic reprogramming of immune cells, regulating the functions of innate immunity [such as macrophage polarization and dendritic cells (DCs) maturation] and adaptive immunity (differentiation of T/B cell subsets and their metabolic changes), and achieving immune responses such as antibody production, cytotoxicity and immune memory. Figure 2. The changes in metabolic pathways of T cells and B cells in the resting and active states. T cells and B cells mainly undergo oxidative metabolism, while mitochondria remain stable in the resting state. Upon activation, the metabolic pathways undergo fundamental changes. Specifically, T cells predominantly tend to undergo aerobic glycolysis, while B cells maintain a relatively high level of OXPHOS. Meanwhile, the associated signaling pathways (such as mTOR, PI3K/AKT, etc.) are activated to support cell proliferation and functional performance. Figure 3. Metabolic reprogramming facilitates T cell differentiation: Subpopulation-specific metabolic pathways involved in viral infections. Th1 cells: Increased glycolysis activated by mTOR/FAO enhances antiviral activity, while viral infections (e.g., HIV) or OXPHOS impairment may disrupt Th1 cell differentiation. Th2 cells: OXPHOS and FAO promote Th2-mediated allergic responses, but excessive glycolysis may inhibit their function. Th17 cells: Glycolysis drives pro-inflammatory differentiation, whereas viral infections (e.g., EBV suppressing glutaminase) or hypoxia (induced by CMV) result in the impairment of Th17 functions. Treg cells: OXPHOS maintains stability, but metabolic stress induced by virus infection inhibits the function of Treg cells. Figure 4. The engagement of metabolic reprogramming of macrophages and dendritic cells in adaptive immunity. The diagram of metabolic reprogramming of macrophages (M1 and M2 types) and dendritic cells (DCs) in response to various signal stimuli, and the secreted cytokines on the effects of polarization and differentiation of Th1 and Th2 cells, revealing the complex interplay between macrophages and DCs on the adaptive immunity. Supplementary Material File (table1.docx) Download 18.73 KB File (table2.docx) Download 18.88 KB File (table3.docx) Download 18.53 KB Information & Authors Information Version history V1 Version 1 30 July 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords b cell dendritic cell macrophage t cell Authors Affiliations Guoshuai Tong Chinese Academy of Agricultural Sciences Harbin Veterinary Research Institute State Key Laboratory for Animal Disease Control and Prevention View all articles by this author Jingwen Dai Chinese Academy of Agricultural Sciences Harbin Veterinary Research Institute State Key Laboratory for Animal Disease Control and Prevention View all articles by this author Qianqian Liu Chinese Academy of Agricultural Sciences Harbin Veterinary Research Institute State Key Laboratory for Animal Disease Control and Prevention View all articles by this author Xu Gao Yanbian University Agriculture College View all articles by this author Su Li 0000-0002-5845-4617 Chinese Academy of Agricultural Sciences Harbin Veterinary Research Institute State Key Laboratory for Animal Disease Control and Prevention View all articles by this author Hua-Ji Qiu [email protected] Chinese Academy of Agricultural Sciences Harbin Veterinary Research Institute State Key Laboratory for Animal Disease Control and Prevention View all articles by this author Metrics & Citations Metrics Article Usage 424 views 222 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Guoshuai Tong, Jingwen Dai, Qianqian Liu, et al. 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