bims-imseme 2026-08-23 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–08–23
fifteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Proteostasis Collapse Drives Effector Memory T Cells Re-expressing CD45RA (TEMRA) Generation in the Tumor Microenvironment.
Nicotinamide Metabolism Constrains Memory CD8+ T Cell Formation Through a Putative HS1BP3-SIRT1-FOXO3-BCL6 Axis.
Tumor-reactive LAG3+CD8+ T cells diverge into terminally exhausted cells and long-lived memory T cells.
Voluntary exercise during weight loss attenuates adipose CD8+ T cell exhaustion that persists after weight regain.
Investigating the role of costimulatory domains in enhancing CAR-T cell persistence in TNBC.
Caloric restriction suppresses colorectal tumors and melanoma through CD8 T cells in aged mice.
Hypoxia induces cytotoxicity and suppresses cytokine production by CD8□ T cells in cutaneous leishmaniasis.
α2,3-sialylation on human naïve T cells restrains bispecific engager-mediated anti-tumor immunity.
Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function.
Impact of sialyltransferase deletion in mature T cells on control of subcutaneous and metastatic cancers.
Tumor-hepatocyte crosstalk drives a hepatic lactate-TGF-β axis of CD8 + T cell exhaustion and immunotherapy resistance in small-cell lung cancer liver metastases.
SAMHD1 enhances HIV-1-induced glycolysis in monocytic cells through hexokinase 2 upregulation.
Evolution and Mechanistic Insights of Immunometabolism in Metabolic Diseases and Infections.
CD8+ stem cell-like memory T cells: Unveiling the potential for next-generation vaccination strategies.
NAD⁺ Circuits in Aging, Tissue Repair and Fibrosis.

Phenomics. 2026 Apr;6(2): 150-167

Proteostasis Collapse Drives Effector Memory T Cells Re-expressing CD45RA (TEMRA) Generation in the Tumor Microenvironment.

Linlin Li, Shuo Kan, Qiang Huang, Shiwen Wang, Yuchen Han, Liang Chen, Jun Jin.

  T cell senescence causes T cell dysfunction in tumors, but its drivers are unclear. Here we found that protein overload in the tumor microenvironment (TME) induces T cell differentiation into effector memory T cells re-expressing CD45RA (TEMRA). TEMRA cells exhibit senescent-like features, including reduced proliferative capacity and expression of senescence-associated markers. Both CD4+ and CD8+ T cells activated under high protein-to-amino-acid-ratio conditions in vitro or within TME niches underwent enhanced TEMRA differentiation. Single-cell transcriptomics showed that protein overload co-activates terminal effector and senescence programs. Mechanistically, it disrupts proteostasis by inhibiting lysosomal and proteasomal degradation, triggering a maladaptive unfolded protein response (UPR) that drives TEMRA commitment. Exogenous amino acid supplementation prevented UPR activation and TEMRA differentiation. In humanized tumors, intra-tumoral amino-acid administration reduced TEMRA accumulation, boosted T cell proliferation, and improved tumor control. Our work reveals managing proteostatic stress as a strategy to counter TEMRA generation and restore anti-tumor immunity.
Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-025-00309-7.

Keywords:  Cellular proteostasis; Effector memory T cells re-expressing CD45RA; Protein overload; Tumor microenvironment

DOI:  https://doi.org/10.1007/s43657-025-00309-7
Adv Sci (Weinh). 2026 Aug 21. e77284

Nicotinamide Metabolism Constrains Memory CD8+ T Cell Formation Through a Putative HS1BP3-SIRT1-FOXO3-BCL6 Axis.

Siyang Wang, Xiaoqian Fan, Yifan Huang, Chang Yao, Jixing Fan, Yu Ping, Xuan Zhao, Congcong Li, Chunyi Shen, Jiqi Shan, Jinyan Liu, Shengdian Wang, Zhen Zhang, Yi Zhang.

  Memory T cells exhibit long-term persistence, a defining feature that underpins durable clinical responses to adoptive immunotherapies. The mechanisms that integrate metabolic cues with transcriptional control of memory fate remain undetermined. Here, we identify HS1-binding protein 3 (HS1BP3) is preferentially expressed in memory CD8+ T cells. HS1BP3 deficiency reduced memory-associated gene expression in CD8+ OT-1 T cells following Listeria monocytogenes-ovalbumin infection and impaired antitumor responses. Loss of HS1BP3 induces metabolic reprogramming characterized by reduced oxidative phosphorylation (OXPHOS) and altered nicotinamide metabolism, accompanied by increased NAD+ and nicotinamide metabolite 1-methylnicotinamide (MNAM) abundance. HS1BP3 interacted with Sirtuin 1 (SIRT1), and its deficiency is associated with increased SIRT1 activity, enhanced Forkhead box O3 (FOXO3) signaling, and reduced expression of memory-associated transcription factor B cell lymphoma 6 (BCL6). Moreover, accumulation of MNAM impairs the antitumor activity of CD8+ T cells. Importantly, elevated levels of HS1BP3 drive chimeric antigen receptor (CAR) -T cells towards a memory phenotype and improve tumor control. Collectively, our findings identify HS1BP3 as a regulator of CD8+ T cell memory and indicate that its effects are associated with alterations in nicotinamide metabolism and the SIRT1-FOXO3-BCL6 signaling axis. These observations support the therapeutic potential of HS1BP3-engineered CAR-T cells across solid tumors.

Keywords:  CD8+ T cell; antitumor response; memory; nicotinamide metabolism

DOI:  https://doi.org/10.1002/advs.77284
J Exp Med. 2026 Sep 07. pii: e20241968. [Epub ahead of print]223(9):

Tumor-reactive LAG3+CD8+ T cells diverge into terminally exhausted cells and long-lived memory T cells.

Vaishali Aggarwal, Yangxi Sun, Chang Liu, Jian Cui, Sasikanth Manne, Yingtong Dou, Qiang Chen, Erin A Brunazzi, Kate M Vignali, Haiguang Wang, E John Wherry, Creg J Workman, Dario A A Vignali.

Chronic T cell stimulation in tumors and chronic viral infections leads to T cell exhaustion, a state of dysfunction. As LAG3 marks a prominent subset of exhausted T (TEX) cells in mid-to-late stage tumors, we generated a Lag3 lineage-tracing mouse model (Lag3iCreERT2Rosa26LSL-tdTomato) to fate map and characterize tumor-reactive LAG3+CD8+ TEX cells. In tumor-bearing mice, two distinct tumor-specific tdTomato+ CD8+ T cell subsets stratified by LAG3 surface expression (LAG3+tdT+ and LAG3-tdT+) exhibited contrasting anatomical distributions, functionality and transcriptional profiles, yet shared TCR clonotypes, suggesting a common origin. While LAG3+tdT+ CD8+ TEX cells were restricted to the tumor microenvironment and predominantly terminally exhausted, LAG3-tdT+ CD8+ TEX cells were progenitors that persisted in vivo and are required for anti-tumor immunity against a secondary tumor challenge. This study highlights TEX cell functional heterogeneity and plasticity and characterizes a unique fate-flexible LAG3-tdT+ progenitor TEX subset that drives an anti-tumor memory response, supporting antibody-based therapeutic targeting of LAG3+ TEX cells to unleash anti-tumor immunity and promote durability.

DOI: https://doi.org/10.1084/jem.20241968
bioRxiv. 2026 Jul 28. pii: 2026.07.25.740730. [Epub ahead of print]

Voluntary exercise during weight loss attenuates adipose CD8+ T cell exhaustion that persists after weight regain.

Okechukwu Kingsley Oforka, Emily C LaVoy, Matthew A Cottam, Munira Kapadia, Emily Nguyen, Caroline Hegemann, Alyssa H Hasty, Nathan C Winn, Heather L Caslin.

Background: Weight gain and loss induce adipose CD8+ T cell exhaustion, which persists and may worsen glucose tolerance following weight regain. Because exercise can reduce T cell exhaustion in the blood, we hypothesized that exercise during weight loss would attenuate adipose CD8+ T cell exhaustion and glucose tolerance following weight regain.
Methods: Male C57Bl/6J mice were fed low-fat or high-fat diets over 8 to 9-week cycles to generate lean, obese, weight loss, or weight cycled groups. Additional weight loss and weight cycled groups were provided exercise wheels during the weight loss phase.
Results: As expected, weight loss increased total and exhausted CD8+ T cells by flow cytometry. Mice that ran the most during weight loss had the lowest proportion of exhausted CD8+ T cells. Notably, exercise reduced the proportion of exhausted CD8+ T cells even after the cessation of exercise and weight regain in all mice. However, exercise did not improve glucose tolerance or macrophage inflammation following weight regain. Moreover, exercise did not affect the induction of innate immune memory in adipose macrophages following weight loss.
Conclusion: The addition of exercise to a weight loss intervention remarkably reduced exhausted CD8+ T cells in the adipose tissue even after the cessation of exercise and weight regain. While exercise did not affect macrophage inflammation or glucose tolerance following weight regain, these results illuminate new questions about the persistence and mechanisms by which exercise reduces tissue CD8+T cell exhaustion and the direct role of macrophages in modulating glucose tolerance with weight cycling.

DOI: https://doi.org/10.64898/2026.07.25.740730
Cancer Gene Ther. 2026 Aug 21.

Investigating the role of costimulatory domains in enhancing CAR-T cell persistence in TNBC.

Hany E Marei, Giacomo Pozzoli, Carlo Cenciarelli.

This work summarizes how costimulatory domains can mediate the persistence, function, and therapeutic potential of CAR-T cells in triple-negative breast cancer (TNBC), a highly aggressive malignancy with limited treatment options and an immunosuppressive tumor microenvironment. Although CAR-T cell therapy has produced remarkable results in hematologic malignancies, its translation to TNBC remains limited by poor T cell persistence, metabolic dysfunction, and rapid exhaustion. Current evidence identifies canonical costimulatory domains (CD28 and 4-1BB) as having differential effects on intracellular signaling, metabolic programming, and T cell differentiation; CD28-based CAR-T cells promote rapid activation and glycolytic metabolism but are commonly associated with terminal differentiation and decreased durability, whereas 4-1BB signaling supports mitochondrial fitness, oxidative phosphorylation, and the development of memory-like T cells that support longer-lasting persistence. The functional differences in CAR-T cells are context-dependent and influenced by antigen density, hypoxia, and other immunosuppressive signals within the TNBC tumor microenvironment. Newer costimulatory domains, such as HVEM and TNFRSF9, have added an additional layer of complexity to T cell signaling by modulating activating and inhibitory pathways, and their incorporation into CAR designs offers new ways to optimally regulate T cell responses; however, their functions are not fully defined in TNBC models. Additionally, dual costimulation strategies and combination therapies (metabolic reprogramming of T cells, epigenetic modulation, and immune checkpoint blockade) have shown promise in preclinical studies, but their translational value remains to be validated. An important message arising from this review is that while persistence may be improved through enhanced costimulatory signaling, the ideal performance of CAR T therapy occurs with the establishment of an ideal balance of stimulating signals that promote the sustained function of effector T cells while inhibiting the exhaustion of T cells and avoiding the deleterious effects of tonic activation. Furthermore, it is critical to evaluate data from TNBC models compared to other solid tumors to inform rational CAR T design strategies in TNBC.

DOI: https://doi.org/10.1038/s41417-026-01073-0
Cell Rep. 2026 Aug 17. pii: S2211-1247(26)00922-8. [Epub ahead of print]45(8): 117844

Caloric restriction suppresses colorectal tumors and melanoma through CD8 T cells in aged mice.

Taichi Horino, Haruki Horiguchi, Daisuke Torigoe, Shinsei Yumoto, Tsuyoshi Kadomatsu, Koh Harada, Michio Sato, Toshiro Moroishi, Masaaki Iwatsuki, Yuichi Oike.

  Caloric restriction (CR) has shown the potential to extend lifespan and reduce cancer risk; however, the mechanisms underlying CR-mediated tumor suppression are not fully understood. Here, we investigate age-dependent CR effects on tumor progression and anti-tumor immune responses in a murine CR model. In aged mice, CR, defined as a 30% reduction in caloric intake, significantly suppressed tumor growth in murine syngeneic models of colorectal cancer or melanoma. CR also enhanced tumor infiltration by CD8+ T cells, which when depleted limited the tumor-suppressive effects of CR in aged mice. RNA-seq analysis of intratumoral CD8+ T cells revealed that CR upregulated the expression of genes associated with T cell function. Furthermore, mechanistic studies of effects of CR on age-related changes in CD8+ T cells, and immunohistochemical analysis suggested that normalization of the vasculature in the tumor microenvironment of aged CR mice is accompanied by decreased expression of angiogenic growth factors secreted by intratumoral CD8+ T cells. Our findings overall provide insight into age-dependent tumor-suppressive effects of CR and illustrate the essential role of CD8+ T cells in CR-mediated tumor suppression.

Keywords:  CP: cancer; CP: immunology; aging; caloric restriction; immune aging; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2026.117844
bioRxiv. 2026 Aug 04. pii: 2026.07.30.741849. [Epub ahead of print]

Hypoxia induces cytotoxicity and suppresses cytokine production by CD8□ T cells in cutaneous leishmaniasis.

Erin A Fowler, Olivia L Schneider, Faaiza Saif, Fernanda O Novais.

Cutaneous leishmaniasis is characterized by chronic inflammatory skin lesions in which CD8□ T cells exhibit paradoxical functions. While IFN-γ-producing CD8□ T cells contribute to the development of protective immunity in the draining lymph node, CD8□ T cells recruited to the infected skin lose their ability to produce IFN-γ and instead acquire cytotoxic functions that exacerbate tissue damage. We previously demonstrated that the hypoxic microenvironment of leishmanial lesions promotes CD8□ T cell cytotoxicity through induction of Blimp-1. Whether hypoxia also suppresses protective CD8□ T cell functions, however, is unknown. Here, we show that hypoxia simultaneously suppresses production of the protective cytokines IFN-γ and TNF-α while enhancing expression of granzyme B and perforin in activated CD8□ T cells. In vitro, HIF-1α, but not HIF-2α, was required for hypoxia-induced expression of granzyme B, perforin, and Blimp-1, whereas suppression of IFN-γ and TNF-α occurred independently of HIF signaling, indicating that distinct oxygen-related pathways regulate pathogenic and protective CD8□ T cell functions. Hypoxia also increased expression of multiple inhibitory receptors on CD8□ T cells, although lesional CD8□ T cells lacked expression of the terminal exhaustion-associated transcription factor TOX, suggesting that hypoxia promotes an inhibitory phenotype distinct from terminal exhaustion. Finally, adoptive transfer studies demonstrated that in vivo both HIF-1α and HIF-2α expression in CD8□ T cells contributed to immunopathology during cutaneous leishmaniasis. Together, these findings identify hypoxia as a key regulator that functionally reprograms CD8□ T cells by promoting pathogenic cytotoxicity while suppressing protective cytokine production within lesions.

DOI: https://doi.org/10.64898/2026.07.30.741849
bioRxiv. 2026 Aug 06. pii: 2026.08.02.742298. [Epub ahead of print]

α2,3-sialylation on human naïve T cells restrains bispecific engager-mediated anti-tumor immunity.

Johanna Nimmerfroh, Dinah Heiligensetzer, Michael Sandholzer, Anastasiya Börsch, Andreas Zingg, Christoph Schultheiss, Mascha Binder, Rafael Martinez Carrasco, Pablo Argüeso, Alfred Zippelius, Luana Guerra, Heinz Läubli.

Aberrantly elevated cell-surface sialylation, or hypersialylation, is a common feature of human cancers and contributes to immune evasion. Sialidase-based therapies have therefore emerged as a strategy to disrupt this glyco-checkpoint. Although the immunosuppressive role of tumor-associated sialylation is well established, how sialylation on human T cells shapes anti-tumor responses remains poorly defined. Here, we identify surface sialoglycans on T cells, particularly α2,3-linked structures, as a cell-intrinsic restraint on human T cell activation, proliferation, and effector function. In vitro , enzymatic desialylation enhanced T cell activation, proliferation, cytokine production, and bispecific T cell engager (TCE)-mediated tumor-cell killing in healthy donor PBMC co-cultures. In ex vivo cultures of primary chronic lymphocytic leukemia (CLL) PBMCs, sialidase treatment combined with the CD20-directed TCE glofitamab enhanced cytotoxic effector transcriptional programming in autologous T cells. Single-cell RNA sequencing combined with lectin-based CITE-seq linked treatment-induced transcriptional states to lectin-defined cell-surface glycan signatures within the same single-cell dataset. This integrated analysis revealed that naïve and, to a lesser extent, central memory T cells combined elevated baseline α2,3-sialylation signatures with the clearest transcriptional responses to glofitamab plus sialidase treatment. CD43 emerged as a major carrier of α2,3-linked sialoglycans, and its deletion attenuated sialidase-enhanced T cell activation. Together, these findings identify sialylation of the T cell surface as a subset-specific restraint on human TCE responses and provide a rationale for testing sialidase-TCE combinations designed to engage less-differentiated T cell populations.
One-sentence summary: Desialylation enhances bispecific T cell engager responses by relieving a sialoglycan-dependent restraint in human T cells.

DOI: https://doi.org/10.64898/2026.08.02.742298
Cell. 2026 Aug 19. pii: S0092-8674(26)00923-2. [Epub ahead of print]

Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function.

Oliver Takacsi-Nagy, Sivakanthan Kasinathan, Austin Hartman, Yajie Yin, Lujing Wu, Andy Y Chen, Laura M Moser, Audre P May, Gabriella C Reeder, Emily Celallos Fuentes, Courtney Kernick, Johnathan Lu, Alison K McClellan, Colin J Raposo, Brendan Terrall, Nicole E Theberath, Patrick K Yan, Peng Xu, Elena Sotillo, Justin Eyquem, Crystal L Mackall, Theodore L Roth, Ansuman T Satpathy.

  Human protein-coding genes evolved via rearrangement of domains from ancestral genes. We develop a scalable, evolutionarily guided method to assemble novel genes from constituent domains within a protein family, termed DESynR (domain engineered via synthesis and recombination) genes. In primary human T cells, DESynR activator protein-1 (AP-1) transcription factors (TFs) significantly outperform natural AP-1 TFs across in vitro and in vivo antitumor assays. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming and establish non-natural T cell states that optimize features of exhaustion, effector and cytotoxic function, and persistence-sometimes co-opting gene modules from disparate cell types. Reprogramming is primarily driven by differential regulation of established AP-1-bound regulatory elements rather than unique binding. Finally, we screen DESynR erythroblast transformation-specific (ETS) and forkhead box (FOX) TFs to support generalizability across protein families. Overall, we demonstrate that reconfiguring existing protein domains may uncover non-evolved genes that program therapeutically relevant cell states.

Keywords:  CAR T cells; genome engineering; synthetic biology; transcriptional regulation

DOI:  https://doi.org/10.1016/j.cell.2026.07.054
Glycobiology. 2026 Aug 19. pii: cwag065. [Epub ahead of print]

Impact of sialyltransferase deletion in mature T cells on control of subcutaneous and metastatic cancers.

Xiaoshuang Wang, James C Paulson.

  To investigate the roles of the α2,3-sialyltransferase ST3Gal1 and the α2,6-sialyltransferase ST6Gal1 in T cell-mediated tumor control, we generated mice with mature T cell-specific deletion of ST3Gal1 (T-ST3KO) or ST6Gal1 (T-ST6KO) using distal Lck-Cre-mediated recombination. Deletion of ST3Gal1 in mature T cells did not affect thymic T cell development but resulted in a reduction of peripheral CD8+ T cells. In contrast, ST6Gal1 deletion had minimal impact on T cell development and peripheral T cell abundance. Following in vitro stimulation of isolated T cells from T-ST3KO and parental wild type (WT) mice with anti-CD3 plus anti-CD28/CD80-Fc, CD8+ T cells from T-ST3KO mice exhibited enhanced activation and an increased frequency of CD44 positive memory-like T cells, while comparison of T cells from T-ST6KO and the parental WT mice showed no significant changes. Despite the activated CD8+ T cell phenotype in T-ST3KO mice, subcutaneous MC38 tumors displayed accelerated growth. In contrast, tumor progression in T-ST6KO mice was unchanged from the parental WT mice. Notably, T-ST6KO mice developed increased pulmonary metastases following intravenous challenge with B16F10 melanoma cells, whereas metastatic burden was unaffected in T-ST3KO mice. These findings demonstrate distinct and non-redundant roles for ST3Gal1- and ST6Gal1-mediated sialylation in regulating T cell function and antitumor immunity and reveal context-dependent effects of T-cell intrinsic sialylation in controlling primary tumor growth and metastatic dissemination.

Keywords:  CD8+ T cell; metastasis; sialic acid; sialyltransferases; tumor

DOI:  https://doi.org/10.1093/glycob/cwag065
bioRxiv. 2026 Jul 31. pii: 2026.07.30.741857. [Epub ahead of print]

Tumor-hepatocyte crosstalk drives a hepatic lactate-TGF-β axis of CD8 + T cell exhaustion and immunotherapy resistance in small-cell lung cancer liver metastases.

Amira Kazi, Yingying Cao, Chirayu Mohindroo, Abhinav Joshi, Yang Zhang, Yue Huang, Chiori Tabe, Brett Schroeder, Thorkell Andersson, Ajit Kumar Sharma, Anish Thomas.

Purpose: Liver metastases confer poor outcomes and attenuate the benefit of immunotherapy across solid tumors. This study investigated how the hepatic metastatic niche promotes CD8⁺ T cell dysfunction and immunotherapy resistance in small-cell lung cancer (SCLC).
Experimental Design: Clinical outcomes and tumor gene expression were integrated with multi-region single-cell RNA sequencing of T cells from rapid-autopsy SCLC metastases, together with spatial transcriptomics. SCLC-hepatocyte conditioned-media models were combined with stable-isotope tracing, mass spectrometry, functional and metabolic assays, and ChIP-qPCR to define mechanisms of CD8⁺ T cell suppression.
Results: Liver metastases were associated with inferior survival and reduced benefit from immune checkpoint blockade. Multi-region single-cell analysis showed that CD8⁺ T cells from liver metastases exhibited an exhaustion-associated state enriched for hypoxia, lactate, and TGF-β programs. SCLC-hepatocyte crosstalk generated a lactate- and TGF-β-rich microenvironment that reduced CD8⁺ T cell effector function, proximal T cell receptor signaling, glycolytic fitness, viability, and proliferation. Stable-isotope tracing demonstrated transfer and accumulation of co-culture-derived lactate in recipient CD8⁺ T cells, with limited entry into downstream pyruvate-linked pathways. Lactate accumulation was accompanied by increased H3K18 lactylation at the PDCD1 , LAG3 , and TGFB1 regulatory loci. In parallel, SCLC-hepatocyte crosstalk increased paracrine TGF-β and activated canonical SMAD2 signaling in CD8⁺ T cells. TGF-β receptor inhibition restored CD8⁺ T cell proliferation. In the phase III IMpower133 cohort, a combined lactate-TGF-β transcriptional program was associated with inferior survival, most strongly in patients with liver metastases.
Conclusions: Tumor-hepatocyte crosstalk generates convergent lactate and TGF-β signals that drive CD8⁺ T cell dysfunction in liver metastases. This hepatic immune-metabolic circuit provides a potential mechanism for immunotherapy resistance and supports therapeutic strategies targeting TGF-β signaling in liver-metastatic SCLC.
Translational Relevance: Patients with SCLC liver metastases have poor outcomes and derive limited benefit from immune checkpoint blockade, but actionable mechanisms of hepatic immune resistance remain undefined. We identify an immune-metabolic circuit in which SCLC-hepatocyte crosstalk generate lactate and TGF-β signals that converge on CD8⁺ T cells. Stable-isotope tracing demonstrates the transfer and accumulation of tumor-hepatocyte-derived lactate in recipient T cells, which causes H3K18 lactylation at exhaustion- and TGFB1-associated loci. In parallel, paracrine TGF-β activates canonical SMAD signaling and reinforces proliferative dysfunction. TGF-β receptor inhibition restores CD8⁺ T cell proliferation. In the phase III IMpower133 cohort, a combined lactate-TGF-β program is associated with inferior survival, particularly among patients with liver metastases. These findings provide a mechanistic and biomarker framework for testing TGF-β-directed strategies in liver-metastatic SCLC, a population with substantial unmet clinical need.

DOI: https://doi.org/10.64898/2026.07.30.741857
bioRxiv. 2026 Aug 04. pii: 2026.08.03.742570. [Epub ahead of print]

SAMHD1 enhances HIV-1-induced glycolysis in monocytic cells through hexokinase 2 upregulation.

Hua Yang, Pak-Hin Hinson Cheung, Li Wu.

SAMHD1 is a mitochondria-associated cellular protein that restricts HIV-1 replication by depleting intracellular dNTP pools in non-dividing immune cells, such as macrophages, dendritic cells, and resting CD4 + T cells; however, its role in host metabolism remains unclear. Building on our previous finding that SAMHD1 promotes mitochondrial membrane damage in HIV-1-infected monocytic cells, here we identify a new function for SAMHD1 in enhancing HIV-1-induced glycolysis through upregulation of hexokinase 2 (HK2). In monocytic THP-1 cells, but not differentiated macrophage-like cells, SAMHD1 amplifies HIV-1-triggered glucose uptake and basal glycolysis. Mechanistically, SAMHD1 increases HK2 expression and promotes its cytosolic accumulation, leading to elevated reactive oxygen species (ROS) production. This SAMHD1-dependent metabolic rewiring links antiviral restriction to glycolytic control and cellular stress responses. Our findings reveal a cell state-specific role for SAMHD1 in regulating glycolysis during HIV-1 infection, identify HK2 as a key effector, and uncover an unanticipated layer of host-virus interaction in monocytic cells.
IMPORTANCE: SAMHD1 is best known as a restriction factor that inhibits HIV-1 replication mainly through its dNTPase activity. However, emerging evidence suggests that SAMHD1 also regulates mitochondrial homeostasis and cellular metabolism. We previously demonstrated that SAMHD1 promotes HIV-1-induced apoptosis in monocytic cells through a mitochondrial pathway, implicating SAMHD1 in the control of mitochondrial function during infection. Because mitochondria are central regulators of cellular energy metabolism, we investigated whether SAMHD1 influences glycolytic reprogramming in HIV-1-infected monocytic cells. Our results show that SAMHD1 enhances glucose uptake, glycolysis, HK2 expression, and ROS production during HIV-1 infection. These findings reveal a previously unrecognized role for SAMHD1 in coordinating metabolic and oxidative stress responses to HIV-1 infection and provide new mechanistic insight into the interplay between antiviral factors, cellular metabolism, and HIV-1 pathogenesis. Understanding how SAMHD1 regulates glucose metabolism may uncover novel links between innate immune defenses and metabolic disease.

DOI: https://doi.org/10.64898/2026.08.03.742570
Scand J Immunol. 2026 Aug;104(2): e70141

Evolution and Mechanistic Insights of Immunometabolism in Metabolic Diseases and Infections.

Wenbin Tan.

  Immunometabolism, an emerging field exploring metabolic reprogramming and functional regulation in immune cells, offers a lens for understanding complex diseases. This review delineates core concepts, key signalling nodes-emphasising the mechanistic target of rapamycin (mTOR) as an integrator of metabolic and immune signals-research and intervention strategies across metabolic and infectious diseases. Immune cells display metabolic plasticity: At rest, they depend mainly on mitochondrial oxidative phosphorylation, but swiftly shift to aerobic glycolysis upon activation to fuel effector functions. Pro-inflammatory subsets like Th1 cells and M1 macrophages lean heavily on glycolysis, whereas regulatory T cells favour fatty acid oxidation. Central pathways-glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism-directly shape immune activation and inflammation via intermediates and regulatory enzymes. For example, succinate and itaconic acid are critical in inflammation control, while fatty acid and cholesterol metabolism dictate immune cell fate. In metabolic disorders such as obesity, diabetes, fatty liver disease, and atherosclerosis, immune metabolic reprogramming is the main driver of chronic low-grade inflammation and tissue injury. During infection, a metabolic tug-of-war ensues: Pathogens hijack host metabolism for survival, and the host counters by reprogramming its own metabolism. The idea of "trained immunity" highlights how metabolism-epigenetics crosstalk endows innate immunity with memory-like capacity. These insights inform therapeutic avenues-modulating metabolic pathways, nutritional interventions, and microbiome targeting-with wide potential. Challenges remain, including the complexity of in vivo networks and the need for precise interventions. Yet advances in single-cell multi-omics and metabolic flux analysis will deepen mechanistic understanding and enable breakthroughs in precision strategies.

Keywords:  immunometabolism; infection; metabolic diseases; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.1111/sji.70141
Cell Rep Med. 2026 Aug 18. pii: S2666-3791(26)00407-6. [Epub ahead of print]7(8): 102990

CD8+ stem cell-like memory T cells: Unveiling the potential for next-generation vaccination strategies.

Laury Nguema, Yves Lévy, Véronique Godot.

  The fields of vaccinology and tumor immunology have long prioritized CD8+ central memory T (Tcm) cells as markers of long-term protection, often neglecting the cell population responsible for the most durable immune memory. Recent advances in T cell biology have clearly established the existence of stem cell-like memory T (Tscm) lymphocytes, now regarded as major emerging contributors. CD8+ Tscm cells are highlighted for their capacity for long-term self-renewal, multipotency, and robust recall responses, features that make them attractive targets in chronic infection and cancer immunotherapy. The real revolution is mechanistic: Tscm cell differentiation follows a defined blueprint integrating a specific metabolic profile, lymphoid niche control, and the T cell receptor (TCR) "Goldilocks principle," tuned by costimulatory networks. This review synthesizes current mechanistic knowledge of Tscm cell induction and discusses how it can guide the rational design of future vaccines and adoptive cell therapies engineered to generate these long-lived populations.

Keywords:  CD8(+) Tscm cells; memory T cells; self-renewal properties; vaccination

DOI:  https://doi.org/10.1016/j.xcrm.2026.102990
Ageing Res Rev. 2026 Aug 17. pii: S1568-1637(26)00297-7. [Epub ahead of print] 103305

NAD⁺ Circuits in Aging, Tissue Repair and Fibrosis.

Reza Izadpanah, Jay Rappaport, Eckhard U Alt.

  Aging remodels compartmentalized nicotinamide adenine dinucleotide (NAD⁺) circuits in ways that influence stress responses, senescence, tissue repair and susceptibility to fibrosis. Beyond its classical role as a redox cofactor, NAD⁺ fuels sirtuins, PARPs and CD38, linking cellular metabolism to chromatin remodeling, DNA repair, calcium signaling and cell fate. A central translational question is whether modulating NAD⁺ in a given tissue and time window will favor regeneration, restrain fibrotic remodeling, or support malignant adaptation. In this review, we define NAD⁺ as a compartmentalized, high-turnover metabolic circuit whose topology, timing and cell-type specificity shape tissue trajectories during aging, repair and fibrosis. We first describe how aging reshapes these circuits through CD38 upregulation, PARP-sirtuin competition, extracellular eNAMPT amplification, and altered mitochondrial NAD⁺ transport, which redistributes NAD⁺ between compartments without necessarily changing bulk tissue concentration. We then summarize how de novo, Preiss-Handler Handler (including niacin/GPR109a) and nicotinamide salvage pathways are organized across nuclear, cytosolic, mitochondrial and extracellular compartments, and how key consumers including sirtuins, PARPs, CD38 and SARM1 govern these pools. We then examine how these circuits operate across acute injury, chronic senescence-associated remodeling, and malignant microenvironments in heart, lung, liver, kidney, skin, muscle and brain. Finally, we integrate emerging human data on NAD⁺ precursors and enzyme-directed strategies and propose a framework for NAD⁺-based interventions that prioritizes timing, compartmental targeting and oncologic stratification.

Keywords:  Aging; Fibrosis; NAMPT; Nicotinamide adenine dinucleotide; Senescence; Tissue repair; eNAMPT

DOI:  https://doi.org/10.1016/j.arr.2026.103305