bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–08–24
fifteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment.
  2. Corrigendum to "Survival of the fittest: Cancer challenges T cell metabolism" [Cancer Lett. 412 (2018) 216-223].
  3. SARDH in the 1-C metabolism sculpts the T-cell fate and serves as a potential cancer therapeutic target.
  4. Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2.
  5. SOX4-ZIP14-zinc metabolism mediates oncogenesis and suppresses T cell immunity in nasopharyngeal carcinoma.
  6. Reprogramming CD8+ T-cell branched N-glycosylation limits exhaustion, enhancing cytotoxicity and tumor killing.
  7. Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8 + T cells underlies distinct functional potential.
  8. An efficient framework to decipher microRNA regulatory programs applied to T cells.
  9. DRP1 downregulation impairs mitophagy, driving mitochondrial ROS and SASP production in rheumatoid arthritis CD4+PD-1+T cells.
  10. 2-Methoxyestradiol Treatment Prevents Graft-versus-Host Disease While Preserving Graft-versus-Leukemia Effect in Mice.
  11. Loss of YTHDF2 enhances Th9 programming and CAR-Th9 cell antitumor efficacy.
  12. A Dual Role for NKG7 in T-cell Cytotoxicity and Longevity.
  13. The mevalonate pathway couples lipid metabolism to amino acid synthesis via ubiquinone-dependent redox control.
  14. Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer.
  15. Dehydration promotes intracellular lipid synthesis and accumulation.
  1. bioRxiv. 2025 Aug 11. pii: 2025.08.07.668717. [Epub ahead of print]
    Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment.
    Mary P Udumula, K M Anjaly, Faraz Rashid, Mohammad Nematullah, Harshit Singh, Tanya Bhardwaj, Miriana Hijaz, Shailendra Giri, Eduardo N Chini E, Heather M Gibson H, Ramandeep Rattan.
      Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg)-mediated immunosuppression. In aged EOC-bearing mice, we observed reduced survival, accompanied by impaired CD4⁺ and CD8⁺T cell responses and a marked expansion of FOXP3⁺ Tregs exhibiting elevated IL-10 and TGFβ expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged mice, along with a fivefold increase in intracellular succinate levels. This accumulation of succinate within the aged tumor microenvironment was found to potentiate Treg suppressive function. Notably, pharmacologic inhibition of α-ketoglutarate dehydrogenase reversed this effect, restoring effector T cell activity. These findings highlight succinate driven metabolic reprogramming as a central mechanism of age related Treg dysfunction in EOC and suggest that targeting succinate metabolism may offer a promising strategy to rejuvenate antitumor immunity in elderly patients.
    DOI:  https://doi.org/10.1101/2025.08.07.668717
  2. Cancer Lett. 2025 Aug 17. pii: S0304-3835(25)00544-0. [Epub ahead of print] 217974
    Corrigendum to "Survival of the fittest: Cancer challenges T cell metabolism" [Cancer Lett. 412 (2018) 216-223].
    Davide G Franchina, Feng Q HeFeng, Dirk Brenner.
      
    DOI:  https://doi.org/10.1016/j.canlet.2025.217974
  3. Cell Mol Immunol. 2025 Aug 20.
    SARDH in the 1-C metabolism sculpts the T-cell fate and serves as a potential cancer therapeutic target.
    Wen Si, Sijin Cheng, Haiyin He, Yu Zhang, Yuhui Miao, Dingcheng Yi, Mengjiao Ni, Anqiang Wang, Hongtao Fan, Yufei Bo, Chang Liu, Zhaode Bu, Linnan Zhu, Zemin Zhang.
      T-cell metabolism plays a pivotal role in defining T-cell functional states. Through analysis of a comprehensive pancancer single-cell transcriptional atlas, we identified SARDH, an enzyme involved in one-carbon (1-C) metabolism, as a potential T-cell metabolic checkpoint. SARDH significantly impacts T-cell fate and function, leading to impaired tumor control efficacy. Knocking down SARDH resulted in sarcosine accumulation and reduced consumption of S-adenosylmethionine (SAM), a critical methyl donor for epigenetic modulation, likely due to the shift in glycine-to-sarcosine homeostasis. Deletion of SARDH increased H3K79me2 modification at NF-κB-activating genes, thereby augmenting NF-κB signaling and T-cell function. Additionally, we observed transcriptional dysregulation of 1-C metabolism within tumors across various cancer types, which was often accompanied by increased sarcosine levels. Sarcosine was found to induce SARDH upregulation, suggesting a feedback mechanism for metabolic homeostasis in T cells within tumors. These findings underscore the potential effects and mechanism of targeting 1-C metabolism, particularly SARDH, as an avenue for cancer therapy.
    Keywords:  1-C metabolism; CD8+ exhausted T cells; Mitochondrial metabolism; SARDH; Sarcosine; Tumor microenvironment
    DOI:  https://doi.org/10.1038/s41423-025-01331-5
  4. Nat Commun. 2025 Aug 16. 16(1): 7644
    Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2.
    Hao Cheng, Fang Nan, Ning Ji, Xiao Ma, Jianan Zhang, Hantian Liang, Wei Zhang, Hiroko Nakatsukasa, Huiyuan Zhang, Wenwen Jin, Hong Jiang, Jiyu Tong, Xikun Zhou, Ning Li, Qi Zhang, Hongbo Hu, WanJun Chen, Hao Xu, Dunfang Zhang.
      CD4+Foxp3+ regulatory T cells are essential for maintaining immune tolerance and preventing excessive inflammation, making them promising candidates for treating autoimmunity and GvHD. However, the translation of regulatory T cell therapy into clinical practice poses substantial challenges. Here, we show that adoptive regulatory T cell therapy increases IL-6 and TGF-β-dependent pathogenic Th17 cell differentiation in murine models of inflammatory bowel disease and experimental autoimmune encephalomyelitis. Regulatory T cells increase the p-stat3/p-stat5 ratio in effector T cells by suppressing IL-2 secretion and competitively consuming IL-2, thereby promoting Th17 cell differentiation. Notably, IL-2 signaling deficiency not only promotes a Th17 cell-associated transcriptional program, but also enhances the pro-inflammatory properties of Th17 cells. Strikingly, therapeutic blockade of IL-6/STAT3 signaling pathway can reverse pathogenic Th17 cell differentiation and enhance the therapeutic effect of regulatory T cell therapy. Thus, our findings could potentially advance the clinical research progress of adoptive regulatory T cell therapy.
    DOI:  https://doi.org/10.1038/s41467-025-62628-7
  5. Cell Rep Med. 2025 Aug 13. pii: S2666-3791(25)00373-8. [Epub ahead of print] 102300
    SOX4-ZIP14-zinc metabolism mediates oncogenesis and suppresses T cell immunity in nasopharyngeal carcinoma.
    Yuma Yang, Qin Liu, Jie Luo, Ziyang Qi, Shanshan Li, Lin Shen, Jishi Li, Xiaona Fang, Jiao Huang, Beilei Liu, Shan Liu, Hongyu Zhou, Lu Bai, Ching Ngar Wong, Baifeng Zhang, Danyang Zheng, Yu Zhang, Wei Dai, Lanqi Gong, Xin-Yuan Guan.
      Subtle variations of micronutrients in the tumor microenvironment often coincide with tumor progression and immune disorders. Nevertheless, the underlying mechanisms of how micronutrients, such as metal ions, influence tumor-intrinsic properties and tumor-immune crosstalk remain inadequately characterized. Here, our integrative analysis of multi-center single-cell, spatial transcriptome sequencing, and bulk RNA sequencing (RNA-seq) cohorts reveals that nasopharyngeal carcinoma (NPC)-specific SRY-box transcription factor 4 (SOX4) governs microenvironmental and cellular zinc metabolism through its downstream target, SLC39A14 (ZIP14), a membrane zinc uptake transporter. Mechanistically, NPC cells enhance zinc uptake and activate Wnt/β-catenin signaling to initiate tumor growth, creating a zinc-deficient niche hostile to T cells. Zinc deficiency of tumor-infiltrating CD8+ T cells impairs LCK phosphorylation and T cell receptor (TCR) signaling, compromising their effector function. Our study elucidates the idea that the SOX4-ZIP14-zinc metabolism axis has a multifactorial effect in NPC, fostering the malignant phenotypes of NPC and suppressing the T cell response through the deprivation of zinc metabolism.
    Keywords:  CD8(+) T cells; LCK signaling; SOX4; ZIP14; immune resistance; nasopharyngeal carcinoma; oncogenesis; tumor microenvironment; zinc metabolism
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102300
  6. Cancer Immunol Res. 2025 Aug 19.
    Reprogramming CD8+ T-cell branched N-glycosylation limits exhaustion, enhancing cytotoxicity and tumor killing.
    Catarina M Azevedo, Bingxian Xie, William G Gunn, Ronal M Peralta, Carolina S Dantas, Henrique Fernandes-Mendes, Supriya Joshi, Victoria Dean, Pedro Almeida, Drew Wilfahrt, Nuno Mendes, Julian López Portero, Carmen Poves, María Jesús Fernández-Aceñero, Ricardo Marcos-Pinto, Ângela Fernandes, Greg M Delgoffe, Salomé S Pinho.
      T-cell therapies have transformed cancer treatment. While surface glycans have been shown to play critical roles in regulating T-cell development and function, whether and how the glycome influences T cell-mediated tumor immunity remains an area of active investigation. In this study, we show that the intratumoral T-cell glycome is altered early in human colorectal cancer, with substantial changes in branched N-glycans. We demonstrated that CD8+ T cells expressing β1,6-GlcNAc branched N-glycans adopted an exhausted phenotype, marked by increased PD1 and Tim3 expression. CRISPR/Cas9 deletion of key branching glycosyltransferase genes revealed that Mgat5 played a prominent role in T-cell exhaustion. In culture-based assays and tumor studies, Mgat5 deletion in CD8+ T cells resulted in improved cancer cell killing. These findings prompted assessment of whether MGAT5 deletion in anti-CD19 chimeric-antigen receptor (CAR) T cells could enable this therapeutic modality in a solid tumor setting. We showed that MGAT5 KO anti-CD19-CAR T cells inhibited the growth of CD19-transduced tumors. Together, these findings show that MGAT5-mediated branched N-glycans regulate CD8+ T-cell function in cancer and provide a strategy to enhance antitumor activity of native and CAR T cells.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0313
  7. bioRxiv. 2025 Aug 11. pii: 2025.08.08.669213. [Epub ahead of print]
    Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8 + T cells underlies distinct functional potential.
    Simone L Park, Mark M Painter, Sasikanth Manne, Victor Alcalde, Maura McLaughlin, Matthew A Sullivan, Divij Mathew, Leonel Torres, Yinghui J Huang, David B Reeg, Naomi R Douek, Trenton Campos, Max Klapholz, Maria A Cardenas, Victoria Fang, Shin Foong Ngiow, K C Wumesh, Rishi R Goel, Amy E Baxter, Jennifer E Wu, Melody Tan, Corbett T Berry, Christoph T Ellebrecht, Alexander C Huang, Emily Papazian, Ying Liu, Karthik Rajasekaran, Robert M Brody, Erica R Thaler, Devraj Basu, Ahmed Diab, Josephine R Giles, E John Wherry.
      Persistent antigen stimulation promotes differentiation of exhausted CD8 + T (T EX ) cells. T EX cells are distinct from circulating memory T (T CIRCM ) cells but share many features with tissue-resident memory (T RM ) cells established following infection resolution. CD8 + T cells co-expressing residency- and exhaustion-associated molecules in chronic diseases often correlate with clinical outcomes. However, the relationship between these cells and conventional T RM or T EX cells remains unclear. Here, we show that chronic antigen stimulation drives development of tissue-resident T EX (TR-T EX ) cells that are ontologically and functionally distinct from T RM cells generated after antigen clearance. TR-T EX phenotypically resembled T RM cells but were regulated by distinct transcriptional networks and were uniquely dependent on Tox for residency programming. Although T EX progenitor cells acquired residency features upon entering chronically infected tissues, they failed to generate conventional T RM cells after antigen withdrawal. Conversely, T RM cells were able to differentiate into T EX cells during chronic antigen stimulation. Deriving cell-state specific transcriptional signatures revealed a selective association of TR-T EX cells with patient responses to immune checkpoint blockade, and only TR-T EX but not T RM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-T EX and T RM cells are developmentally distinct cell types that share a tissue-residency program but have distinct roles in disease control.
    DOI:  https://doi.org/10.1101/2025.08.08.669213
  8. Genes Immun. 2025 Aug 18.
    An efficient framework to decipher microRNA regulatory programs applied to T cells.
    Hongya Zhu, Divya Ganapathi Sankaran, Norah L Smith, Ciarán W P Daly, Kristel Yee Mon, Cybelle Tabilas, Erin M Wissink, Brian D Rudd, Andrew Grimson.
      Naïve CD8 + T cells are heterogenous, with subsets exhibiting divergent kinetics and functions post-activation. MicroRNAs, important mediators of post-transcriptional regulation, contribute to specification of different naïve T cell subsets. However, the microRNA regulatory circuits mediating functional specialization of naïve subsets are poorly understood. Here, we profiled microRNA expression in diverse subsets of naïve CD8 + T cells, revealing significant differences in their microRNA expression landscapes. We developed a novel framework, miR-Inf, to decipher microRNA regulatory programs. miR-Inf features two innovative attributes: (i) an efficient approach based on intron-exon ratios to estimate gene decay rates from a compendium of RNA-seq profiles, in order to better capture microRNA regulatory effects, and (ii) identification of cell-type-specific microRNA targets by integrating decay rate data and microRNA expression data. We applied this framework to identify consequential miRNAs in naïve CD8 + T cell subsets and predicted their subset-specific targets. Our analyses revealed that miR-29, a microRNA known to be important in CD8 + T cells, likely functions by modulating transcripts encoding epigenetic factors, thereby pre-programming different naïve T cell subsets to exhibit different immune responses post-activation. Collectively, our data and broadly applicable framework defined microRNA regulatory circuits across a variety of naïve CD8 + T cell subsets.
    DOI:  https://doi.org/10.1038/s41435-025-00351-5
  9. Redox Biol. 2025 Aug 09. pii: S2213-2317(25)00331-3. [Epub ahead of print]86 103818
    DRP1 downregulation impairs mitophagy, driving mitochondrial ROS and SASP production in rheumatoid arthritis CD4+PD-1+T cells.
    Ziran Bai, Jinyi Ren, Jiaqing Liu, Cheng Zhang, Huina Huang, Xiangge Zhao, Xianmei Chen, Jing Wei, Jingjing Qi, Siwen Yang, Weiping Li, Yawei Tang, Guan Wang, Xia Li.
      T cell senescence occurs in patients with rheumatoid arthritis (RA), but the specific phenotype and its contribution to tissue-destructive inflammation remain unclear. Here, we aim to investigate whether PD-1 marks pathogenic senescent CD4+T cells and to explore the role and mechanism of senescent CD4+PD-1+T cells in RA pathogenesis. Here, we identified an expanded population of CD4+PD-1+T cells in RA patients that exhibited hallmark senescence features, including elevated senescence-associated secretory phenotype (SASP) production. Adoptive transfer experiments demonstrated that CD4+PD-1+T cells significantly accelerated disease progression in collagen-induced arthritis (CIA) models. Mechanistically, we demonstrated that RA CD4+PD-1+T cells showed decreased expression of dynamin-related protein 1 (DRP1) and impaired mitophagy, leading to mitochondrial reactive oxygen species (MtROS) accumulation and subsequent SASP production. Importantly, PD-1 signaling transcriptionally suppressed DRP1 expression through hypoxia inducible factor 1 alpha subunit (HIF-1α) inhibition. Our findings establish CD4+PD-1+T cells as a pathogenic senescent subset that drives RA progression through a PD-1-DRP1-mitophagy-SASP axis.
    Keywords:  CD4(+)PD-1(+)T cells; Dynamin-related protein 1; Mitochondrial reactive oxygen species; Rheumatoid arthritis; Senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1016/j.redox.2025.103818
  10. bioRxiv. 2025 Aug 11. pii: 2025.08.11.667504. [Epub ahead of print]
    2-Methoxyestradiol Treatment Prevents Graft-versus-Host Disease While Preserving Graft-versus-Leukemia Effect in Mice.
    Dan Li, Roland Bassett, Richard E Champlin, Jeffrey J Molldrem, Tak W Mak, Qing Ma.
      2-Methoxyestradiol (2ME2, Panzem) is an endogenous metabolite that is well-tolerated in phase I/II clinical trials for variety of tumors. The plasma levels of 2ME2 may increase up to 1,000-fold during pregnancy and correlate temporally with the remission of rheumatoid arthritis (RA) and multiple sclerosis (MS) symptoms. The anti-inflammatory properties of 2ME2 were recently established in the mouse model of MS, and the mechanism of action is the ability of 2ME2 to inhibit lymphocyte proliferation, cytokine production and T cell polarization. Herein, we have demonstrated that 2ME2 treatment can significantly reduce the mortality and morbidity associated with graft-versus-host disease (GVHD). There is a lower number of donor-derived CD4 + and CD8 + T cells in the peripheral lymph node and Peyer's patches of 2ME2-treated mice compared to control recipients. Moreover, 2ME2 exposure can significantly decrease the production of IFN-γ and IL-2 in donor-derived CD4 + T cells and serum in GVHD mice. However, 2ME2 treatment has no effect on the differentiation of CD8 + effector T cells in vivo and their cytolytic activity remains intact. Furthermore, 2ME2 therapy is effective in preventing GVHD while preserving graft-versus leukemia (GVL) activity in mice. Our findings indicate that 2ME2 could be a novel and effective treatment for GVHD patients.
    DOI:  https://doi.org/10.1101/2025.08.11.667504
  11. Nat Immunol. 2025 Aug 18.
    Loss of YTHDF2 enhances Th9 programming and CAR-Th9 cell antitumor efficacy.
    Sai Xiao, Songqi Duan, Yaqun Hong, Jianying Zhang, Shoubao Ma, Michael A Caligiuri, Jianhua Yu.
      CD4+ T cells differentiate into various subsets, including T helper 1 (Th1), Th2, Th9, Th17 and regulatory T (Treg) cells, which are essential for immune responses and cancer immunotherapy. However, the role of RNA N6-methyladenosine (m6A) modification in this differentiation is unclear. Here we show that YTHDF2, an important m6A reader protein known to destabilize m6A-modified mRNA, negatively regulates Th9 cell differentiation. Ablation of Ythdf2 in both mouse and human naive CD4+ T cells promotes Th9 differentiation by stabilizing Gata3 and Smad3 mRNA under interleukin-4 (IL-4) and transforming growth factor β (TGF-β) signaling, respectively. Ythdf2-deficient Th9 cells produce increased amounts of IL-9 and IL-21, leading to increased tumor infiltration and cytotoxicity by CD8+ T cells and natural killer (NK) cells, thereby improving antitumor activity compared with wild-type Th9 cells. Moreover, YTHDF2 depletion in CAR-Th9 cells enhances their immune activation, reduces their terminal differentiation and augments their antitumor efficacy. Targeting YTHDF2 is thereby a promising strategy to enhance Th9 and CAR-Th9 cell-based cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41590-025-02235-2
  12. Cancer Immunol Res. 2025 Aug 18. OF1-OF6
    A Dual Role for NKG7 in T-cell Cytotoxicity and Longevity.
    Haidong Dong, Hyoungjun Ham, Whitney Barham, Ti Wen, Jacob B Hirdler, Zhiming Mao, Dallin S Ashton, Wenjing Zhang, Fabrice Lucien-Matteoni, Henrique Borges da Silva, Daniel D Billadeau.
      The effectiveness of T cell-based immunotherapy depends on durable T-cell responses that can efficiently eliminate tumor cells. NKG7 was discovered three decades ago as a protein associated with lytic granules. However, only studies published over the past 5 years have contributed substantially to our understanding of NKG7 in T-cell biology. NKG7 has been recognized as an important T-cell functional marker in responses to immune checkpoint inhibitor therapy and in the prognosis of certain cancers. Besides its role in the generation, trafficking, and release of lytic granules, which is critical for efficient T-cell cytotoxicity against tumor cells, NKG7 has been identified as a key negative regulator of mTORC1 activity. By restraining mTORC1 activity, NKG7 promotes T-cell longevity and memory generation after infection. Importantly, NKG7 upregulation has demonstrated therapeutic potential in preclinical T-cell therapy for cancer. Collectively, NKG7 is emerging as a promising biomarker and therapeutic addition to T cell-based immunotherapies.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0384
  13. bioRxiv. 2025 Aug 12. pii: 2025.08.10.669191. [Epub ahead of print]
    The mevalonate pathway couples lipid metabolism to amino acid synthesis via ubiquinone-dependent redox control.
    Thi Thinh Nguyen, Mohit Bansal, Jane Ding, Sunil Sudarshan, Han-Fei Ding.
      The mevalonate pathway produces sterols and isoprenoids that support cancer cell growth, yet its broader metabolic functions remain incompletely defined. Here, we show that this pathway sustains amino acid biosynthesis by promoting mitochondrial NAD⁺ regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impairs oxidative phosphorylation, lowers the NAD⁺/NADH ratio, and suppresses de novo serine and aspartate synthesis, thereby activating the GCN2-eIF2α-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limits purine and pyrimidine nucleotide production. Expression of the bacterial NADH oxidase LbNOX or the alternative oxidase AOX restores NAD⁺ levels and rescues statin-induced growth inhibition. These findings suggest that impaired NAD⁺ regeneration is a key mechanism contributing to the anti-proliferative activity of statins, linking the mevalonate pathway to mitochondrial electron transport- dependent control of amino acid metabolism.
    Significance: This study identifies the mevalonate pathway as a regulator of amino acid biosynthesis through mitochondrial electron transport-dependent NAD⁺ regeneration and reveals redox disruption as a key mechanism contributing to the anti-proliferative effects of statins.
    DOI:  https://doi.org/10.1101/2025.08.10.669191
  14. Cell Rep Med. 2025 Aug 13. pii: S2666-3791(25)00374-X. [Epub ahead of print] 102301
    Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer.
    M Angela Aznar, Charly R Good, Julie S Barber-Rotenberg, Sangya Agarwal, Wesley Wilson, Alex Watts, Zhen Zhang, Donna Gonzales, Greg Donahue, Wei-Ting Hwang, Austin K Rennels, Andrew J Rech, Shunichiro Kuramitsu, Hua Huang, Karl M Glastad, Katherine A Alexander, Gabriela Plesa, Emily Dowd, Andrea Brennan, Donald L Siegel, Janos Tanyi, Andrew Haas, Drew A Torigian, Gregory Nadolski, Vanessa E Gonzalez, Elizabeth O Hexner, Joseph A Fraietta, Julie K Jadlowsky, Regina M Young, Shelley L Berger, Carl H June, Mark H O'Hara.
      Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a median survival of less than a year, highlighting the urgent need for treatment advancements. We report on a phase 1 clinical trial assessing the safety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients with advanced PDAC. While therapy is well tolerated, it demonstrates limited clinical efficacy. Analyses of patient samples provide insights into mechanisms of treatment resistance. Single-cell genomic approaches reveal that post-infusion CAR T cells express exhaustion signatures, including previously identified transcription factors ID3 and SOX4, and display enrichment for a GZMK+ phenotype. Single knockout of ID3 or SOX4 enhances efficacy in xenograft models, though with donor-dependent variability. However, single-knockout cells eventually fail. Conversely, ID3 and SOX4 double-knockout CAR T cells exhibit prolonged relapse-free survival, demonstrating a sustained therapeutic effect and a potential avenue for engineering more potent CAR T cells in PDAC. This study was registered at ClinicalTrials.gov (NCT03323944).
    Keywords:  CAR T cells; ID3; SOX4; T cell dysfunction; T cell exhaustion; cancer; clinical trial; immunotherapy; pancreatic cancer; single-cell RNA-seq
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102301
  15. bioRxiv. 2025 Aug 11. pii: 2025.08.07.669190. [Epub ahead of print]
    Dehydration promotes intracellular lipid synthesis and accumulation.
    Joshua S Carty, Jazlyn Selvasingh, Yvonne Zuchowski, Hyuck-Jin Nam, Clothilde Pénalva, Gayani Nanayakkara, Erin Q Jennings, Kelsey Voss, Edith T Adame, John T Tossberg, Wei Sheng Yap, Meiling Melzer, Olga Viquez, A Scott McCall, Elizabeth R Piotrowski, Ryoichi Bessho, Shirong Cao, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, Simona G Codreanu, Stacy D Sherrod, John A McLean, Jonathan B Trapani, Matthew A Cottam, Ma Wan, Deepti Shrivastava, Don Delker, Matthew H Wilson, Clinton M Hasenour, Louise Lantier, Irene Chernova, Jamey D Young, Volker H Haase, Jose Pablo Vazquez-Medina, Dylan K Kosma, Peter Kim, Jean-Philippe Cartailler, Mingzhi Zhang, Roy Zent, Raymond C Harris, Jason A Watts, Andrew S Terker, Fabian Bock, Jeffrey C Rathmell, Aylin R Rodan, Juan P Arroyo.
      Lipids can be considered a water reservoir used to offset dehydration stress as their oxidation by the mitochondria generates water. However, whether dehydration directly regulates lipid synthesis is unknown, which is the focus of this study. We found that dehydration stress decreases cellular oxygen consumption, increases intracellular lipid synthesis, and favors glutamine oxidation as a carbon precursor for lipid synthesis via remodeling mitochondrial metabolism. These findings provide a mechanism whereby cellular dehydration leads to intracellular lipid accumulation, functionally linking water availability to lipid storage.
    DOI:  https://doi.org/10.1101/2025.08.07.669190
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