bims-imseme 2026-01-11 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–01–11
thirty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Active aldehydes drive metabolic exhaustion in CD8+ T cells.
Nutritional intervention alleviates T cell exhaustion and empowers anti-tumor immunity.
Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment.
Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion.
CAR-T Cell Exhaustion in Cancer over the Past Decade: Mitochondrial Metabolism as a Target for Counteraction.
ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors.
Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function.
The LXRβ/NF-κB axis reprograms CAR-T cells to resist exhaustion in the tumor microenvironment.
CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency.
Exercise Ameliorates Immunosenescence: From Mechanisms to Interventions.
CD38 promotes LPS-induced innate-like activation and proliferation of CD8+ T lymphocytes in aged mice.
SLC2A1+ tumour-associated macrophages spatially control CD8+ T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.
CRISPR/Cas strategies to enhance CAR T-cell function and persistence via metabolic reprogramming.
Immunometabolism of T cells and macrophages: Human translational perspectives.
TMEM33 deletion potentiates anti-tumor CD8 + T cell immunity.
Interleukin-7R and chemokine receptor type 7 differentially regulate metabolism in CD4+ and CD8+ T cells.
Metabolic Reprogramming of T Cells by Dual UCP2 and IL-17 Blockade Enhances Immunity Against Pancreatic Cancer.
PD-1 regulates CD4+ T cell-mediated CD8+ T cell responses in the brain to balance viral control and neuroinflammation.
Post-COVID impairment of memory T cell responses to community-acquired pathogens can be rectified by activating cellular metabolism.
DNA-PKcs controls the cytotoxic T cell response to cancer and transplant allograft through regulating LAT-dependent signaling.
Mitochondrial asymmetry shifts T cell fate.
Aging kidney is associated with metabolic rewiring and epigenetic reprogramming.
Engineering T Cells with Membrane-Anchored Nitric Oxide Scavengers for Anticancer Therapy.
TIGIT disruption rescues the antitumor activity of low avidity TCR-engineered T cells by increasing TCR signal strength.
Recharging cellular immunotherapy - targeting immunometabolic aging.
Allospecific splenic Tr1 cells drive effector T cell exhaustion through up-regulated Areg-EGFR signaling to promote transplant tolerance.
Microbiota utilization of intestinal amino acids modulates cancer progression and anticancer immunity.
Brain-infiltrating CD8 T cells retain functional activity to protect against acute Zika virus infection.
A distinct subset of stem-cell memory is poised for the cytotoxicity program in CD4+ T cells in humans.
IL-21 enhances the cytotoxicity of intratumoral CD8+ T cells improving radiation efficacy.
Engineering single-vector logic-gated CAR T cells with transgene sizes beyond current limitations.
ERα activates NAMPT/IL-33 signaling to enhance beige thermogenesis and metabolic fitness.

Nat Immunol. 2026 Jan 08.

Active aldehydes drive metabolic exhaustion in CD8+ T cells.

DOI: https://doi.org/10.1038/s41590-025-02413-2
Front Immunol. 2025 ;16 1689317

Nutritional intervention alleviates T cell exhaustion and empowers anti-tumor immunity.

Yuqi Xu, Wenhui Yuan, Ke Li, Peng Li.

  T cells are central mediators of adaptive immunity, playing a pivotal role in eliminating pathogens and tumor cells. In the context of chronic infections and cancer, however, persistent antigenic stimulation drives T cells into a state of exhaustion characterized by diminished effector function, sustained expression of inhibitory receptors, and profound metabolic reprogramming. Emerging evidence indicates that T cell exhaustion is not irreversible and can be alleviated through immune checkpoint blockade, such as targeting PD-1. Moreover, increasing attention has been directed toward the role of intracellular metabolic pathways in shaping T cell fate and function. Strategies aimed at enhancing nutrient availability and metabolic fitness offer an additional avenue to restore T cell activity. This review highlights recent advances in reversing T cell exhaustion through immune checkpoint inhibitors and nutritional interventions, providing novel insights into the precision and personalization of cancer immunotherapy.

Keywords:  antitumor immunity; exhausted T cells; immune checkpoint inhibitors; immunotherapy; nutrients

DOI:  https://doi.org/10.3389/fimmu.2025.1689317
Nat Immunol. 2026 Jan 07.

Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment.

Yasuharu Haku, Koji Kitaoka, Koki Ichimaru, Tomoko Hirano, Jun Wang, Kazuhiro Sonomura, Asuka Maruo, Shuhei Hirose, Yu Wang, Katsuhiro Ito, Tomohiro Kozuki, Keiko Yurimoto, Mai Kiyono, Hidetaka Kosako, Toshi Menju, Hiroshi Date, Takashi Kobayashi, Koichi Omori, Tomonori Yaguchi, Tasuku Honjo, Kenji Chamoto.

Glycolysis and mitochondrial fatty acid oxidation (FAO) regulate CD8+ T cell differentiation, but how this metabolic balance regulates T cell exhaustion is unclear. PD-1 signaling inhibits glycolysis and enhances FAO. Here, we show that CD8+ T cells in tumors adhere to glycolysis with attenuated FAO despite high PD-1 expression. Active aldehydes, final products of lipid peroxidation, accumulate in CD8+ T cells in proportion to their level of exhaustion, defined by mitochondrial mass and potential. Aldehydes promote glycolysis and inhibit FAO in T cells. Mice deficient in an FAO enzyme in T cells generate more acrolein, a representative aldehyde, enhancing T cell exhaustion and attenuating antitumor immunity. Acrolein is generated partly from mitochondria and damages mitochondrial architecture. Inhibitors of lipid peroxidation or aldehydes enhanced PD-1-blockade by rectifying metabolic imbalance. Therefore, active aldehydes resulting from FAO impairment can cause a vicious cycle of metabolic imbalance that leads to T cell exhaustion.

DOI: https://doi.org/10.1038/s41590-025-02370-w
Signal Transduct Target Ther. 2026 Jan 01. 11(1): 2

Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion.

Yiran Wu, Yuchen Wu, Zhengyu Gao, Weixing Yu, Long Zhang, Fangfang Zhou.

T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments, severely compromising the effectiveness of antitumor and antiviral immunity. In recent years, there has been significant progress in understanding the underlying mechanisms of T cell exhaustion, including external factors and intrinsic cellular changes that drive this dysfunctional state. Key external factors such as persistent antigen exposure, immune checkpoint signaling, and the cytokine milieu, as well as intrinsic changes such as altered metabolic processes, epigenetic modifications, and transcriptional reprogramming, contribute to T cell dysfunction. Emerging therapies targeting T cell exhaustion aim to restore immune function and enhance antitumor and antiviral immunity. These therapeutic strategies include immune checkpoint inhibition, cytokine therapies, metabolic reprogramming, and cell-based therapies. Despite these advancements, reversing T cell exhaustion presents several challenges, such as individual variability, resistance, and potential side effects. Furthermore, accurately assessing markers of T cell functional recovery and the long-term impacts of these therapeutic approaches remain challenging research areas. This review provides an overview of the history and milestones in T cell exhaustion research; summarizes the mechanisms of T cell exhaustion and its implications in cancer, chronic infections, and autoimmune diseases; discusses advancements and challenges in emerging therapies; and explores future research directions aimed at improving T cell function and enhancing immune responses.

DOI: https://doi.org/10.1038/s41392-025-02327-3
Cancer Lett. 2026 Jan 02. pii: S0304-3835(26)00003-0. [Epub ahead of print]639 218240

CAR-T Cell Exhaustion in Cancer over the Past Decade: Mitochondrial Metabolism as a Target for Counteraction.

Lingling Si, Di Wei, Jinghao Pan, Renato B Baleeiro, Louisa S Chard Dunmall, Yaohe Wang.

  Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a transformative advancement in cancer immunotherapy, but remains limited by multiple challenges. The exhaustion of T cells represents a critical obstacle limiting the success of immunotherapeutic interventions. Targeting mitochondrial metabolism offers a promising approach to mitigate exhaustion and enhance CAR-T persistence. Mechanistically, mitochondrial dysfunction within the tumor microenvironment disrupts energy metabolism, reactive oxygen species (ROS) homeostasis, and cell survival, impairing CAR-T function. Here, we review the current challenges facing the clinical application of CAR-T therapy in cancers and summarize mitochondrial-centered approaches to overcome some of these obstacles by optimizing mitochondrial metabolic pathways. We emphasize the essential role of mitochondrial metabolism in augmenting therapeutic efficacy and persistence of CAR-T cells. Future breakthroughs will depend on robust clinical evidence and precise metabolic modulation to enhance CAR-T therapies.

Keywords:  CAR-T therapy; Combination therapy; Metabolic reprogramming; Mitochondrial metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2026.218240
Cancers (Basel). 2025 Dec 22. pii: 34. [Epub ahead of print]18(1):

ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors.

Alex Wade Song, Xiaotong Song.

  CAR T cell therapy, while highly effective for hematological malignancies, continues to face significant hurdles in the treatment of solid tumors. Key challenges include severe nutrient deprivation and the presence of immunosuppressive metabolites such as adenosine in the tumor microenvironment, which limit CAR T cell persistence and antitumor activity. This review focuses on current progress and future directions for ADA1-based metabolic reprogramming as a targeted approach to enhance CAR T cell function. We discuss recent advances, particularly the engineering of CAR T cells to express ADA1, which facilitates the local conversion of immunosuppressive adenosine into inosine, thereby supporting T cell metabolism and improving therapeutic outcomes. Preclinical studies, including our own, demonstrate that ADA1-expressing CAR T cells exhibit reduced exhaustion, greater metabolic flexibility, and enhanced antitumor efficacy in solid tumor models. The selective clearance of adenosine and supplementation of inosine directly address the metabolic barriers within the tumor microenvironment and provide an effective strategy to bolster CAR T cell responses. Integration of ADA1-driven metabolic refueling with future innovations in CAR design holds promise for overcoming key obstacles in solid tumor immunotherapy. We conclude by highlighting the potential of ADA1-based strategies and offering our perspective on their translation toward clinical application.

Keywords:  CAR T cells; adenosine; adenosine deaminase; inosine; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers18010034
bioRxiv. 2025 Dec 22. pii: 2025.12.20.695732. [Epub ahead of print]

Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function.

Armin Gandhi, Kathryn Lande, Yichen Li, Filipe A Hoffman, Michael LaPorte, Shirong Tan, Garrett Evensen, Benji Portillo, Marcos Garcia Teneche, Rouven Arnold, Adarsh Rajesh, Jessica Proulx, Shanshan Yin, Aaron Havas, Charlene Miciano, Qian Yang, Elizabeth Smoot, Sainath Mamde, Andrew Davis, Kevin Yip, Allen Wang, Bing Ren, April Williams, Susan Kaech, Peter D Adams.

Liver cancer incidences increase dramatically beyond 55 years of age, suggesting that age-associated changes contribute critically to tumor initiation. However, the mechanisms linking liver aging and cancer initiation are not well defined. This study investigates the role of CD44, a marker of liver tumor-initiating cells (TIC), in age-associated liver pathophysiology. Aged livers showed accumulation of CD44-expressing hepatocytes exhibiting enrichment of immune modulatory genes and activation of the immunosuppressive IL6/JAK/STAT3 pathway. Indeed, in adoptive transfer assays, antigen-exposed CD8+ T cells mounted a lower IFN-γ response in aged livers than in young livers, indicating an immunosuppressive aged milieu. Concordantly, spatial analyses showed that the proximal neighbourhoods of Cd44 -expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knock out of Cd44 mitigated the IL6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL6/JAK/STAT3 pathway and this is associated with impaired T cell effector function.

DOI: https://doi.org/10.64898/2025.12.20.695732
Oncoimmunology. 2026 Dec 31. 15(1): 2611615

The LXRβ/NF-κB axis reprograms CAR-T cells to resist exhaustion in the tumor microenvironment.

Minji Lim, Sang-Eun Jung, Choong-Hyun Koh, Hyungwoo Jeong, Youngchae Moon, Hyungseok Seo.

  Liver X receptor β (LXRβ) is a key transcription factor involved in lipid metabolism and immune regulation, yet its functional role in tumor-infiltrating T cells remains largely unresolved. While LXRβ has been shown to suppress NF-κB target gene expression, the mechanistic interaction between LXRβ and NF-κB signaling in the tumor microenvironment (TME) has not been fully established. In this study, we identify LXRβ as a critical regulator of CAR-T cell differentiation, the metabolic state, and effector function within solid tumors. LXRβ overexpression altered the transcriptional and phenotypic landscape of CAR-T cells, including the modulation of stem-like TCF1⁺ populations, proliferative capacity (Ki-67), and cytokine production (IFNγ, TNFα). Through genetic perturbation of NF-κB components, particularly RelB, we further demonstrate that disrupting non-canonical NF-κB signaling enhances CAR-T cell cytotoxicity and attenuates exhaustion-related features such as TOX upregulation. Notably, combined targeting of LXRβ and RelB produced additive and, in some settings, synergistic benefits, improving metabolic fitness, reducing terminal exhaustion, and augmenting anti-tumor activity in vivo. Together, these findings define an LXRβ-NF-κB regulatory axis that shapes CAR-T cell fate and function in the TME and highlight this pathway as a promising target for improving CAR-T cell-based therapies against solid tumors.

Keywords:  Chimeric Antigen Receptor T-cell (CAR-T); LXRβ; NF-κB; cancer immunotherapy

DOI:  https://doi.org/10.1080/2162402X.2025.2611615
Nat Cancer. 2026 Jan 06.

CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency.

Philip Bucher, Nadine Brückner, Jule Kortendieck, Melanie Grimm, Jan T Schleicher, Karlotta Bartels, Steffen Hardy, Martina Rausch, Hannah Wurzer, Meike Thiemann, Celina May, Mara Mitstorfer, Dennis Letzgus, Julia Quach, Carolin Schneider, Denis A Ispan, Irene Gonzalez-Menendez, Nayan Jain, Yu-Jui Ho, Jiangqing Chen, Francisco J Sánchez-Rivera, Jie Sun, Leticia Quintanilla-Martinez, Christoph Trautwein, Bettina Weigelin, Manfred Claassen, Michel Sadelain, Judith Feucht, Josef Leibold.

Insufficient functional T cell persistence impedes therapeutic success of chimeric antigen receptor (CAR) therapies. Here we performed a CAR-adapted base-editing screen of PIK3CD, a key regulator of T cell function, metabolism and fate. We identified point mutations that beneficially modulate CAR T cell profiles in 4-1BBz and 28z CAR T cells, respectively. We found that point mutations with differing effects on phosphatidylinositol-3-kinase delta (PI3Kδ) signaling activity were advantageous in distinct CAR contexts: The PI3Kδ-activating substitution E81K enhanced proliferation, metabolic fitness and effector function of 4-1BBz CARs, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo. Conversely, the PI3Kδ-attenuating substitution L32P improved T cell memory formation and functionality of 28z CAR T cells. Together, our approach of rational optimization of activation-dependent signaling through targeted allelic reprogramming (ROADSTAR) illustrates the importance of CAR design-specific fine-tuning of intrinsic T cell signaling and demonstrates the potential of base editing for next-generation cellular therapies.

DOI: https://doi.org/10.1038/s43018-025-01099-7
Biology (Basel). 2025 Dec 28. pii: 58. [Epub ahead of print]15(1):

Exercise Ameliorates Immunosenescence: From Mechanisms to Interventions.

Haili Xiao, Jianchang Ren.

  Aging is an inevitable biological process that affects the function of various organs, including the immune system. Immunosenescence is characterized by diminished immune cell function, weakened immune responses, and imbalances in immune components, which together reduce the body's resistance to pathogens and increase the risk of age-related diseases in older adults. These conditions pose direct threats to health and significantly impact quality of life and longevity. Therefore, effective strategies to delay aging and maintain immune function are critical areas of research. Emerging evidence suggests that moderate physical activity can significantly enhance immune system functionality, serving as an effective intervention for mitigating immunosenescence. Exercise is known to remodel the metabolism of carbohydrates, fats, and proteins, strengthen communication between organs and the immune system, regulate the functions of both innate and adaptive immune cells, and decrease age-related chronic inflammation. Furthermore, exercise aids in restoring the functionality of aging immune cells through mechanisms such as autophagy activation, mitochondrial optimization, and epigenetic reprogramming. Importantly, a dose-response relationship exists between various exercise modalities and the attenuation of immunosenescence in older adults, with the cumulative amount of lifelong physical activity profoundly influencing the pace of immunosenescence.

Keywords:  adaptive immunity; aging; exercise; health interventions; immunosenescence; innate immunity; metabolism

DOI:  https://doi.org/10.3390/biology15010058
Front Aging. 2025 ;6 1701685

CD38 promotes LPS-induced innate-like activation and proliferation of CD8+ T lymphocytes in aged mice.

Wendolaine Santiago-Cruz, Enrique Espinosa, Jocelyn C Pérez-Lara, Héctor Romero-Ramírez, Priyadharshini Devarajan, Fabio García-García, Juan C Rodríguez-Alba.

  CD38 is a transmembrane glycoprotein involved in NAD+ metabolism, calcium signaling, and immune cell activation. Its role in the inflammatory response has been studied extensively in innate immune cells; however, its contribution to the activation of memory T lymphocytes under inflammatory conditions is less understood. Additionally, recent studies have shown an age-related increase in the expression of the protein CD38 in various human and murine tissues. Moreover, CD8+ bystander T cells have been shown to contribute to inflammation during the aging process. Given the importance of its potential role in age-related pathologies, we examined the effect of CD38 on bystander activation of CD8+ memory T cells in aged mice following lipopolysaccharide challenge. CD38-deficient mice exhibited attenuated serum cytokine responses (IL-1β, IL-6, IFN-γ, and IL-10) and a distinct CD8+ T cell profile, characterized by a decrease in activated T cells. Wild-type mice displayed a significant expansion of CD69+TCM cells after LPS inoculation, an effect that was absent in CD38-deficient animals. LPS also promoted the expression of CD69 and CD38 in TEM/EFF subsets. Thus, our findings reveal a CD38-dependent mechanism underlying bystander activation of memory CD8+ T cells in aging. Highlighting the potential contribution of CD38 to age-related diseases, such as autoimmunity, and in the face of inflammatory conditions in aged people.

Keywords:  CD38; CD8+ T cells; T cell subsets; aging; bystander activation; inflammaging; lipopolysaccharide

DOI:  https://doi.org/10.3389/fragi.2025.1701685
Nat Cell Biol. 2026 Jan 07.

SLC2A1+ tumour-associated macrophages spatially control CD8+ T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.

Lei Wang, Han Chu, Degao Chen, Yuxuan Wei, Jia Jia, Liqi Li, Linfeng He, Lina Peng, Fangfang Liu, Shanshan Huang, Zheng Jin, Dong Zhou, WenFeng Fang, Tao Jiang, Shouxia Xu, Xiaofang Ding, Haoyang Cai, Xindong Liu, Qingzhu Jia, Bo Zhu, Qian Chu.

Tumour-associated macrophages (TAMs) contribute to immune checkpoint blockade resistance, but their impact on intratumoural CD8⁺ T cell distribution remains unclear. Here we show that the expression of the glucose transporter SLC2A1 is spatially negatively correlated with CD8⁺ T cell distribution in both non-small-cell lung cancer (NSCLC) biopsies and murine tumour models. Tumour cell-specific Slc2a1 knockdown fails to reproduce the therapeutic benefit of SLC2A1 inhibition, whereas TAM-specific deletion of Slc2a1 suppresses tumour growth by enhancing the spatial homogeneity and effector function of intratumoural CD8⁺ T cells, thereby improving αPD-L1 efficacy. Spatial profiling of NSCLC specimens further revealed that SLC2A1⁺ TAM-enriched regions exhibit reduced CD8⁺ T cell density, and spatial proximity between these populations predicts resistance to αPD-(L)1 therapy. These findings identify SLC2A1⁺ TAMs as drivers of spatial CD8⁺ T cell exclusion and highlight TAM-specific SLC2A1 as a therapeutic target to overcome immune checkpoint blockade resistance in NSCLC.

DOI: https://doi.org/10.1038/s41556-025-01840-5
Trends Biotechnol. 2026 Jan 05. pii: S0167-7799(25)00499-8. [Epub ahead of print]

CRISPR/Cas strategies to enhance CAR T-cell function and persistence via metabolic reprogramming.

Margaret R Wang, Wenli Mu, Anjie Zhen, Scott G Kitchen.

  While chimeric antigen receptor (CAR) T-cell therapy has become a standard of care in various blood cancers, its full curative potential for other diseases has yet to be maximized. One key limiting factor is progressive T-cell exhaustion and differentiation over time, leading to the loss of the CAR-expressing cells. CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein) gene manipulation to enhance CAR T-cell therapy has revolutionized the field in recent years. In this review, we will examine the application of CRISPR/Cas aimed at improving CAR T-cell function and persistence to combat the issues of exhaustion and dysfunction, with a focus on metabolic reprogramming. Understanding current preclinical CRISPR/Cas strategies for modulating CAR T-cell metabolism is critical in advancing CAR-T therapies to clinical applications.

Keywords:  CAR-T; CRISPR/Cas; exhaustion; metabolism; persistence

DOI:  https://doi.org/10.1016/j.tibtech.2025.12.001
Immunobiology. 2025 Dec 27. pii: S0171-2985(25)00285-2. [Epub ahead of print]231(1): 153151

Immunometabolism of T cells and macrophages: Human translational perspectives.

Borros Arneth.

   BACKGROUND: Immunometabolism explores how immune-cell function depends on cellular energy metabolism. Recent insights demonstrate that nutrient utilization dictates activation, polarization, and tolerance.
AIMS: To systematically review human studies on T-cell and macrophage metabolism, identify converging pathways, and outline translational implications for inflammation, autoimmunity, and cancer.
METHODS: Following PRISMA 2020 guidelines, PubMed was searched (2015-2025) using predefined MeSH terms ("immunometabolism", "T lymphocytes", "macrophages", "metabolic reprogramming"). Of 999 records, 67 met inclusion criteria (human data, peer-reviewed, quantitative endpoints). Bias was assessed with ROBIS.
RESULTS: Effector T cells and M1 macrophages favor glycolysis for rapid ATP and pro-inflammatory signaling, whereas memory T cells and M2 macrophages rely on oxidative phosphorylation and fatty-acid oxidation for sustained energy and tolerance. mTORC1/AMPK signaling, glutaminolysis, and the kynurenine pathway integrate metabolic and immune cues. Metabolic dysregulation in obesity or tumor microenvironments skews these pathways, driving chronic inflammation or immune escape.
CONCLUSIONS: Human immunometabolism is defined by dynamic substrate switching. Targeting glycolysis, FAO, or tryptophan metabolism offers therapeutic leverage in cancer and autoimmune disease. Future directions include single-cell and spatial metabolomics and integrative metabolic-immune modeling.

Keywords:  Immunometabolism; Inflammation; Macrophages; Metabolic reprogramming; PRISMA review; T cells

DOI:  https://doi.org/10.1016/j.imbio.2025.153151
bioRxiv. 2026 Jan 02. pii: 2026.01.01.697288. [Epub ahead of print]

TMEM33 deletion potentiates anti-tumor CD8 + T cell immunity.

Matthew T Jackson, Tianming Zhao, Gusztav Milotay, Isabela Pedroza-Pacheco, Yanshu Cai, Claire Willis, Su M Phyu, Bruno Beernaert, Jamie Tw Kwon, Hala Estephan, Vinnycius Pereira Almeida, Maria Aggelakopoulou, Silvia Panetti, Christian Zierhut, Tim Elliott, Eleni Adamopoulou, Jan Rehwinkel, Malcolm Jw Sim, Amit Grover, Dmitry I Gabrilovich, Benjamin P Fairfax, Eric Honoré, David R Withers, John C Christianson, Eileen E Parkes.

Improving responses to cancer immunotherapies requires deeper insight into the cellular mechanisms governing T cell-mediated anti-tumor immunity. TMEM33 is an endoplasmic reticulum-resident transmembrane protein enriched across multiple tumor types, with reported functions in anti-viral immunity as well as calcium and lipid homeostasis, yet its role in tumor immunosurveillance remains unknown. Using murine genetic models, we demonstrate that host TMEM33 constrains anti-tumor CD8 + T cell responses. Constitutive Tmem33 -/- mice exhibited delayed melanoma tumor growth and increased CD8 + T cell infiltration. Antigen-specific CD8 + compartments in tumors of Tmem33 -/- mice showed TCF-1 + PD-1 + progenitor-exhausted cell (Tpex) enrichment, elevated effector function and reduced exhaustion, alongside improved effector memory expansion and T-bet expression in draining lymph nodes. We highlight that TMEM33 functions intrinsically within the T cell compartment, as TMEM33 deletion (1) enhanced polyclonal activation of naive CD8 + T cells ex vivo , (2) promoted preferential Tpex accumulation among adoptively transferred naive OT-I cells in B16F10-OVA tumors and draining lymph nodes, and (3) improved the potency of ex vivo -expanded OT-I cells in controlling tumor growth during adoptive cell therapy. Finally, in a large, prospectively recruited metastatic melanoma cohort, lower TMEM33 expression in patient CD8 + T cells significantly correlated with improved survival and elevated TCF-7 (encoding TCF-1). Collectively, our findings define TMEM33 as a formerly unrecognized intrinsic determinant of tumor-directed CD8 + T cell fate that limits Tpex maintenance, and restrains cell therapy responses, suggesting that its modulation may strengthen immunotherapeutic efficacy.
One sentence summary: TMEM33 intrinsically limits progenitor exhausted CD8 + T cells, scales anti-tumor responses and predicts melanoma patient survival.

DOI: https://doi.org/10.64898/2026.01.01.697288
Immunohorizons. 2026 Jan 06. pii: vlaf071. [Epub ahead of print]10(1):

Interleukin-7R and chemokine receptor type 7 differentially regulate metabolism in CD4+ and CD8+ T cells.

Kimberly A Morrissey, Miriam Valenzuela-Cardenas, Rebekah Gridley, Maria Gabaldon-Parish, Anthony Languit, Judy L Cannon.

  Naïve T cells are highly metabolically active, maintaining homeostatic function as well as continuously moving and surveying lymph nodes for dendritic cells (DCs) presenting cognate antigen. T-cell metabolism is thought to change throughout development: Naïve T cells have been found to predominantly utilize catabolism for naïve T-cell homeostasis while T-cell activation leads effector T cells to become glycolytic. There is still relatively less known about how individual and combinations of molecular signals drive specific metabolic programs in naïve T cells. Naïve T cells primarily depend on IL-7 signaling to IL-7R for homeostasis and are driven by the chemokine receptor CCR7 responding to CCL21 for rapid motility in lymph nodes, leading to T-cell surveillance. We identify specific roles for IL-7R and CCR7 in driving differential metabolic programs in naïve CD8+ and CD4+ T cells. We find that while IL-7 treatment increases glycolysis in both naïve CD4+ and CD8+ T cells, CCL21 treatment does not affect glycolysis. Instead, CCR7 signaling decreases respiratory capacity and mitochondrial intensity and area. While IL-7 treatment does not impact overall oxidative phosphorylation, IL-7 also alters mitochondrial dynamics. Interestingly, a combination of IL-7R and CCR7 signaling using IL-7 with CCL21 differentially affects CD4+ versus CD8+ T-cell metabolism. Our results demonstrate that multiple molecular signals can differentially regulate naïve CD4+ and CD8+ T-cell metabolism, leading to changes in both glycolysis and oxidative phosphorylation in naïve T cells.

Keywords:  CCR7; IL-7; chemokines; immunometabolism

DOI:  https://doi.org/10.1093/immhor/vlaf071
Adv Sci (Weinh). 2026 Jan 04. e13020

Metabolic Reprogramming of T Cells by Dual UCP2 and IL-17 Blockade Enhances Immunity Against Pancreatic Cancer.

Chuan-Teng Liu, Chun-Chieh Yeh, Tsai-Chen Wu, Chia-Hsin Lin, Yi-Ting Kuo, Yoichiro Iwakura, Yuan-Ji Day, Charles Drake, Vedran Radojcic, Ying-Chyi Song, Heng-Hsiung Wu, Hung-Rong Yen.

  Pancreatic ductal adenocarcinoma (PDAC) remains resistant to immunotherapy due to its immunosuppressive tumor microenvironment (TME) and impaired metabolic fitness of effector T cells. Here, we show that targeting UCP2 reprograms T-cell metabolism, and that dual blockade with IL-17 further enhance antitumor responses in PDAC. Pharmacologic UCP2 inhibition with genipin increases IFN-γ production by CD8⁺ T cells through IL-12R/STAT4/mTOR signaling and enhanced mitochondrial oxidative phosphorylation, promoting a T-bet-driven cytotoxic program. However, UCP2 inhibition alone does not suppress tumor growth. Accordingly, combination with IL-17 depletion synergistically augments Tc1/Th1 responses, reduces myeloid-derived suppressor cells (MDSCs), and improves survival across multiple PDAC models, including genetically engineered and orthotopic systems. CD8⁺ T-cell depletion abrogates these effects. Moreover, UCP2 inhibition enhances IFN-γ production in patient-derived PBMCs and tumor-infiltrating lymphocytes. These findings identify UCP2 as a metabolic checkpoint in cytotoxic T cells and support dual UCP2/IL-17 blockade as a promising immunotherapeutic strategy for PDAC.

Keywords:  cytotoxic T cell; immunotherapy; interleukin‐17; pancreatic cancer; uncoupling protein 2

DOI:  https://doi.org/10.1002/advs.202513020
Res Sq. 2025 Dec 12. pii: rs.3.rs-8215051. [Epub ahead of print]

PD-1 regulates CD4+ T cell-mediated CD8+ T cell responses in the brain to balance viral control and neuroinflammation.

Aron Lukacher, Arrienne Butic, Elia Afanasiev, Samantha Spencer, Mofida Abdelmageed, Anirban Paul, Kalynn Alexander, Katelyn Ayers, Todd Schell, Matthew Lauver, Ge Jin, Samantha Borys, Laurent Brossay, Jo Anne Stratton, Vonn Walter.

Programmed cell death protein 1 (PD-1) is expressed by T cells during progressive multifocal leukoencephalopathy (PML), a life-threatening brain disease caused by the human-only JC polyomavirus. Why PD-1 blockade finds variable success in PML patients is unclear. Brain CD4+ and CD8+ T cells are PD-1high during mouse polyomavirus (MuPyV) encephalitis. Here, we show that PD-1 loss during MuPyV infection acts in a brain-autonomous manner to increase the magnitude of brain-infiltrating CD4+ and CD8+ T cells and the function of virus-specific CD8+ T cells; in concert, brain virus levels decline and neuroinflammation increases. Deletion of PD-1 in CD4+ T cells, but not CD8+ T cells, recapitulates effects of global PD-1 loss. Single-cell RNA sequencing shows that PD-1-deficient CD8+ T cells cluster as effectors while transcripts associated with proliferation and function are upregulated with loss of PD-1. Thus, CD4+ T cell-intrinsic PD-1 signaling balances antiviral defense against neural injury during polyomavirus CNS infection.

DOI: https://doi.org/10.21203/rs.3.rs-8215051/v1
bioRxiv. 2026 Jan 02. pii: 2025.12.31.697156. [Epub ahead of print]

Post-COVID impairment of memory T cell responses to community-acquired pathogens can be rectified by activating cellular metabolism.

Daniel D Carroll, Kamacay Cira, Jack Archer, Jason Shapiro, Ue-Yu Pen, David Tieri, Lucia Leonor, Neda D Roofchayee, Samantha S Yee, Marc Wahab, Igor J Koralnik, John C Alverdy, Arjun S Raman, Lavanya Visvabharathy.

Infection rates involving bacterial and viral pathogens have increased precipitously after the COVID-19 pandemic. While it has been speculated that higher infection rates resulted from increased hospitalizations throughout the pandemic or greater use of antibiotics, precisely why rates remain high today has remained unexplained. Mitochondrial dysfunction is known to occur post-COVID and may disrupt immune responses. Within T cells, SARS-CoV-2 infection is linked to low mitochondrial membrane potential, increased mitochondrial apoptosis, and decreased mitochondrial respiration, which together impact cellular activation and function beyond the acute phase of illness. Here, we demonstrate that decreased mitochondrial function in antigen-specific T cells post-COVID may contribute to higher infection susceptibility by metabolically immobilizing T cell memory responses. Using donor-matched peripheral blood samples from 31 COVID-naïve individuals who subsequently contracted COVID-19, we tracked how influenza A (IAV), Staphylococcus aureus (SA), and Varicella-zoster virus (VZV) T cell responses were impacted by COVID-19 infection. We found that gene expression linked to T cell activation decreased but mitochondrial redox pathways increased in CD4 memory T cells post-COVID. However, mitochondrial flux and reactive oxygen species production were limited in a plurality of post-COVID memory T cells after stimulation with IAV, SA, and VZV. Furthermore, we found a disordered relationship between memory T cell mobilization of glycolysis, fatty acid metabolism, and oxidative phosphorylation pathways post-COVID which resulted in diminished use of catabolic pathways including glycolysis and fatty acid oxidation in antigen-specific T cells. Modulation of mitochondrial function with metformin and ubiquinol partially rescued the post-COVID decline in T cell catabolism. Collectively, these findings indicate that COVID-19 infection may have lasting effects on inhibiting T cell memory responses to commonly encountered community-acquired pathogens which can be corrected with commonly available medications. This has significant implications for the clinical care of immunologically vulnerable populations in the post-pandemic era.

DOI: https://doi.org/10.64898/2025.12.31.697156
Cell Rep. 2026 Jan 06. pii: S2211-1247(25)01568-2. [Epub ahead of print]45(1): 116796

DNA-PKcs controls the cytotoxic T cell response to cancer and transplant allograft through regulating LAT-dependent signaling.

Randall R Rainwater, Ana C Azevedo-Pouly, Zachary J Waldrip, Belle H Hicks, Nicholas A Callais, Brian Koss, Aaron J Storey, Lyle Burdine, Marie Schluterman Burdine.

  Formation of the immune synapse (IS) following T cell antigen recognition includes recruitment of the linker for activation of T cells (LAT). Once at the IS, LAT tyrosines are phosphorylated, allowing it to serve as a scaffold for the formation of the "signalosome," a multiprotein complex that drives T cell receptor signaling. Here, we show that upon T cell activation, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) interacts with LAT and localizes to the IS. Inhibition of DNA-PKcs diminishes LAT localization at the IS. We identified two LAT serines phosphorylated by DNA-PKcs, S224 and S241, that impact LAT tyrosine phosphorylation, protein binding, and cytokine production. Using our mouse model designed to delete DNA-PKcs expression in mature CD4+ or CD8+ T cells, we show that loss of DNA-PKcs results in T cells that are unable to control tumor growth or induce allogeneic graft rejection. These data highlight DNA-PKcs as a pivotal protein in T cell function.

Keywords:  CD4(+) T cells; CD8(+) T cells; CP: immunology; DNA protein kinase catalytic subunit; DNA-PKcs; LAT; T cell receptor; T cell signaling; TCR; immune synapse; linker for activated T cells; signalosome

DOI:  https://doi.org/10.1016/j.celrep.2025.116796
Nat Cell Biol. 2026 Jan 05.

Mitochondrial asymmetry shifts T cell fate.

Sarah May Russell, Mirren Charnley.

DOI: https://doi.org/10.1038/s41556-025-01841-4
Geroscience. 2026 Jan 07.

Aging kidney is associated with metabolic rewiring and epigenetic reprogramming.

Pragney Deme, Rhea Bhargava, Heddwen L Brooks, Norman J Haughey, Prerna Kumar.

  Understanding the direct connections between metabolism and chromatin dynamics may uncover potential mechanisms involved in the aging process of renal physiology. Despite known differences in incidence and aging renal disease, how biological aging intersects with renal metabolism and epigenetics in a sex-specific context remains poorly understood. Here, we determined the effect of age on renal metabolic pathways and metabolite cofactors of epigenetic modifiers in a sex-specific manner. We measured metabolites in kidney homogenates from young and aged mice by HPLC-TripleTOF (LC-MS). The major metabolic adaptations observed with aging include increased glycolysis, decreased fatty acid oxidation, mitochondrial dysfunction, oxidative stress, and impaired metabolic waste clearance in 24-month-old (aged) mice compared to 4-month-old (young) sex-matched mice. Additionally, we found elevated levels of methylation and acetylation of intermediate metabolites also known as 'epimetabolites' in aged mice. Furthermore, age-related alterations were detected in metabolites (acetyl-coenzyme A, flavin adenine dinucleotide, and α-ketoglutarate) that are essential cofactors for the activities of epigenetic enzymes. Sex-specific changes were observed with age such as, significantly enhanced amino acid catabolism and tryptophan metabolism and reduced lysophospholipase activity and ammonia clearance in aged female vs aged male mice. Our results reveal age- and sex-associated alterations in renal metabolic pathways, characterized by an increase in epigenetically modified intermediate metabolites with aging. These findings suggest a complex interplay between renal metabolomics and epigenetics and offer new insights into the mechanisms underlying sex-specific renal physiology of aging kidneys.

Keywords:  Epimetabolites; Metabolite cofactors for epigenetic enzymes; Metabolomics; Renal aging; Sex differences

DOI:  https://doi.org/10.1007/s11357-025-02071-0
ACS Nano. 2026 Jan 08.

Engineering T Cells with Membrane-Anchored Nitric Oxide Scavengers for Anticancer Therapy.

Jihye Lee, Yeoul Kang, Seonwoo Kang, Hyungjin Sun, Heeyeon Yoon, Junsang Doh, Won Jong Kim.

  T cells are fundamental for orchestrating cancer-specific cytotoxic responses that are central to the success of immune-activation-related cancer therapy. However, the immunosuppressive tumor microenvironment (TME) undermines the effectiveness of T cell therapy by inducing dysfunction and promoting apoptosis of infiltrated T cells. Considering that nitric oxide (NO) is abundantly present in the immunosuppressive TME and acts as a mediator of T cell dysfunction, we aimed to modulate the NO levels within the local T cell environment to enhance the efficacy of T cell therapy. We designed membrane-fusible NO-scavenging liposomes (LipoNOX) to regulate intracellular NO accumulation in T cells within the TME. LipoNOX, which is composed of o-phenylenediamine-containing lipids and 1,2-dioleoyl-3-trimethylammonium-propane, effectively integrated into the plasma membrane and protected the T cells from NO-mediated protein modifications, including S-nitrosylation and tyrosine nitration. LipoNOX-engineered T cells (NOX-T cells) exhibited a revival of proliferation and activation in immunosuppressive TME-mimicking in vitro conditions without compromising their physiological integrity. This functionality significantly augmented the efficacy of T cell therapy in the B16-F10-OVA mouse model of tumor by increasing the population and activity of tumor-infiltrating T cells, thus providing a solid foundation for strategies targeting NO modulation in T cells.

Keywords:  T cell engineering; fusogenic liposome; membrane anchoring; nitric oxide; tumor microenvironment

DOI:  https://doi.org/10.1021/acsnano.5c06907
Nat Commun. 2026 Jan 08.

TIGIT disruption rescues the antitumor activity of low avidity TCR-engineered T cells by increasing TCR signal strength.

Martina Spiga, Alessia Potenza, Zulma Magnani, Stefano Beretta, Barbara Camisa, Laura Conte, Alessia Airaghi, Neda Mohammadi, Laura Perani, Claudio Doglioni, Maurilio Ponzoni, Francesca Sanvito, Chiara Balestrieri, Lucia Sergi Sergi, Oronza A Botrugno, Giulio Giovannoni, Giovanni Tonon, Danilo Abbati, Chiara Iozzi, Maximilian Reichert, Hana Algul, Arianna Pocaterra, Martina Fiumara, Samuele Ferrari, Alessia Ugolini, Alice Grometto, Giulia Di Lullo, Giovanni Sitia, Giulio Belfiori, Maria Pia Protti, Renato Ostuni, Anna Mondino, Michele Reni, Stefano Crippa, Massimo Falconi, Luigi Naldini, Eliana Ruggiero, Chiara Bonini.

T-cell avidity is a major determinant of Adoptive T cell therapy (ACT) efficacy for cancer treatment. However, high-avidity tumor-specific T cells can rarely be isolated from cancer patients, highlighting the need for strategies to enhance the cytotoxic capacity of low-avidity cells. Here, we rescue the anti-tumor functions of low-avidity T cells against pancreatic ductal adenocarcinoma (PDAC) by knocking-out TIGIT, a key inhibitory molecule expressed on exhausted CD8+ T cells infiltrating gastrointestinal tumors. We uncover that TIGIT disruption by base editing boosts the intracellular signal transduction derived from a weak T cell receptor (TCR) engagement enforcing cytoskeletal rearrangements, thus increasing T cell avidity and stabilizing the immunological synapse. Accordingly, TIGIT disruption enables low-avidity T cells to exert robust degranulation, comparable to that of high-avidity T cells, and potent and durable anti-tumor capacity in vivo in male mice. These results highlight TIGIT knockout as a potential strategy to enhance low-avidity T cell function and broaden the repertoire of TCR engineered T cells in the treatment of pancreatic cancer and other solid malignancies.

DOI: https://doi.org/10.1038/s41467-025-67263-w
Immunotherapy. 2026 Jan 07. 1-2

Recharging cellular immunotherapy - targeting immunometabolic aging.

Kathrine Rallis, Alexandra Pommier, Abhishek Singh, José Cancelas.



Keywords:  CAR T cells; Immunotherapy; aging; cancer; cellular therapy; metabolism

DOI:  https://doi.org/10.1080/1750743X.2025.2607468
Sci Adv. 2026 Jan 09. 12(2): eaea0567

Allospecific splenic Tr1 cells drive effector T cell exhaustion through up-regulated Areg-EGFR signaling to promote transplant tolerance.

Amar Singh, Adam Herman, Devanjan Dey, Samuel Menge, Shilpi Singh, Anna Tran, Anders Matson, Ahmed Mourad, Parthasarathy Rangarajan, Ravi Masuria, Naoya Sato, Sarah Vadnais, Joseph Sushil Rao, Gatikrushna Singh, Melanie L Graham, Sabarinathan Ramachandran, Bernhard J Hering.

Inducing stable tolerance to transplants remains a challenge in immunology. Previously, we induced tolerance to allogeneic islets in nonhuman primates by preemptive alloantigen delivery to antigen-presenting cells in situ. Here, mass cytometry phenotyping with incorporated donor-derived MHC-I peptide-loaded MHC-II tetramers revealed accumulation of allospecific CD4+ T cell clusters in the spleen of tolerant recipients. Areg+Tr1 regulatory and terminally exhausted EGFRhi T (Tex) cells represented the predominant allospecific subsets. Trajectory analysis showed that antigen-experienced effector memory T cells differentiated into suppressive Areg+Tr1 and EGFR+TOX+Nur77+TCF-1- Tex subsets. Cell-cell communication mapping showed that exhausted and effector memory T cells engaged with allospecific Tr1 cells via the Areg-EGFR axis. Gene silencing studies confirmed that Tr1 cells use Areg-EGFR signaling to drive the metabolic suppression and epigenetic reprogramming of CD4+ T cells through a Nur77-dependent pathway. These findings point to the splenic Areg+Tr1 cell-EGFR+Teff cell axis as a critical immunoregulatory pathway in peripheral transplant tolerance.

DOI: https://doi.org/10.1126/sciadv.aea0567
Cell Host Microbe. 2026 Jan 02. pii: S1931-3128(25)00522-0. [Epub ahead of print]

Microbiota utilization of intestinal amino acids modulates cancer progression and anticancer immunity.

JRI Live Cell Bank Consortium

  The human microbiota modulates cancer progression through largely unexplored mechanisms. Defining causal pathways is essential for monitoring and fine-tuning the microbiota to improve cancer treatment. Given that amino acid (aa) metabolism is often dysregulated in cancer, we assessed the role of microbiota pathways that modulate intestinal aa levels on colorectal tumor progression in mice. We found that the Bacteroides gene bo-ansB affects tumor responses to dietary asparagine (Asn) by reducing intestinal Asn levels. In mice receiving dietary Asn, bo-ansB promotes tumor progression by altering tumor-infiltrating CD8+ T cells. Mechanistically, bo-ansB depletes Asn in the tumor microenvironment (TME), suppressing the expression of an Asn transporter (SLC1A5) in CD8+ T cells and impairing their stem-like properties and effector functions. In humans, microbiota-encoded genes contributing to aa depletion are associated with colorectal cancer progression. Collectively, these findings reveal nutrient-dependent modulation of anticancer immunity by the gut microbiota and identify diet-microbiota-cancer crosstalk as a potential therapeutic target.

Keywords:  Bacteroides asparaginase; CD8 T cell; amino acid transporter SLC1A5; antitumor immunity; asparagine; diet-microbiota-cancer crosstalk; gut microbiota; host-microbe interactions; microbial amino acid metabolism

DOI:  https://doi.org/10.1016/j.chom.2025.12.003
Sci Rep. 2026 Jan 05.

Brain-infiltrating CD8 T cells retain functional activity to protect against acute Zika virus infection.

Jaehui Kim, Wooseong Lee, Do Yeon Kim, Keun Bon Ku, Young-Chan Kwon, Kyun-Do Kim, Chonsaeng Kim, Dae-Gyun Ahn, Seong-Jun Kim, Sungjun Park.

  Zika virus (ZIKV) infection can cause severe neurological complications, yet the role of CD8+ T cells in controlling viral pathogenesis in the brain remains unclear. Using Ifnar1-/- mice, which lack type I interferon signaling, we demonstrate that ZIKV infection triggers significant infiltration of CD8+ T cells into the brain, accompanied by neurological defects. ZIKV-experienced CD8+ T cells exhibit enhanced cytotoxic potential, and adoptive transfer of these cells improves survival. In contrast, blocking their infiltration exacerbates brain inflammatory and injury-associated signatures, highlighting their protective contribution. Furthermore, PD-1 blockade worsens ZIKV pathology, suggesting that PD-1 expression reflects an activated rather than exhausted state. These findings underscore an important role of infiltrating CD8+ T cells in reducing ZIKV-induced CNS inflammation and suggest that modulating their response could serve as a potential therapeutic strategy for ZIKV-associated neurological disease.

Keywords:   Ifnar1 −/− mouse model; Acute infection; CD8+ T cells; Cytotoxicity; Immune cell infiltration; Neuroinflammation; T cell trafficking; Zika virus (ZIKV)

DOI:  https://doi.org/10.1038/s41598-026-35079-3
Sci Adv. 2026 Jan 09. 12(2): eady6423

A distinct subset of stem-cell memory is poised for the cytotoxicity program in CD4+ T cells in humans.

Raunak Kar, Shreya Sinha, Zainab Khatun, Anjali Sharma, Veena S Patil.

The CD4+ cytotoxic T lymphocytes (CD4-CTLs) with cytotoxic potential are reported to be the components of protective immune response in many diseases. However, the lack of understanding about their lineage, molecular character, and cytolytic potential in comparison to CD8+(CD8)-CTLs has restricted their utility. Thus, here, by parallelly analyzing the human peripheral CD4-CTLs and CD8-CTLs, we demonstrate that they are indistinguishable for the cytotoxic program. Furthermore, using an integrative multiomics approach combining the transcriptome, T cell antigen-receptor repertoire, and open chromatin profile of CD4+ T cell memory subsets, we found a stem-cell memory subset that is precommitted to the cytotoxicity program. Through an in vitro differentiation model, we developed CD4+ T cells with cytolytic potential coexpressing and exhibiting progressive chromatin accessibility for cytotoxicity- and longevity-associated genes, hence generating long-lived CD4-CTL effectors of varying cytotoxic capacity. Together, our study advocates for exploring both CD4-CTLs and CD8-CTLs for vaccine development, vaccine efficacy testing, and immunotherapies and cell-based therapies for precision medicine.

DOI: https://doi.org/10.1126/sciadv.ady6423
JCI Insight. 2026 Jan 08. pii: e190531. [Epub ahead of print]

IL-21 enhances the cytotoxicity of intratumoral CD8+ T cells improving radiation efficacy.

Xinyang Li, Xueqi Xie, Baochao Wei, Xiaozheng Sun, Minxin Chen, Rufei Liu, Qingxu Tao, Yiheng Huang, Qian Wang, Shuangshuang Ma, Ling Wei, Rong Xiao, Zhaoyun Liu, Jinming Yu, Meng Wu, Dawei Chen.

  Radiotherapy is a critical modality in cancer treatment, not only to eradicate cancer cells but also to trigger anti-tumor immunity. Interleukin-21 (IL-21), an immunomodulatory cytokine with potential in cancer therapy, has unexplored synergy with radiotherapy. Our study, leveraging human cancer databases and tissue microarrays, identified a positive correlation between IL-21 and radiotherapy outcomes, particularly in tumor microenvironment (TME) activation. In mouse tumor models, IL-21 combined with radiation significantly enhances TME, boosting CD8+ T cell activation and function, reducing tumor burden, and extending survival. Single-cell transcriptome sequencing revealed that the combination of IL-21 and radiation increased the cytotoxicity of effector and memory CD8+ T cells and prevented their exhaustion. These effects were further validated in humanized mice, where IL-21 combined with radiation reduced A549 tumor growth and enhanced CD8+ T cell function. Post-neoadjuvant radiotherapy samples from patients with esophageal cancer showed a positive correlation between IL-21 levels and CD8+ T cell infiltration. Our findings suggest that IL-21 is a promising adjuvant to radiotherapy, potentially improving the treatment efficacy through TME enhancement. This study provides a foundation for future clinical exploration of IL-21 for enhancing radiotherapy.

Keywords:  Cancer immunotherapy; Oncology; Radiation therapy; T cells; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.190531
J Immunother Cancer. 2026 Jan 09. pii: e012318. [Epub ahead of print]14(1):

Engineering single-vector logic-gated CAR T cells with transgene sizes beyond current limitations.

Philipp C Rommel, Nils W Engel, Julia K Malachowski, Divanshu Shukla, Isabella R Hodson, Donna Gonzales, Johannes C M van der Loo, Regina M Young, James L Riley, Bruce L Levine, Carl H June.

   BACKGROUND: Engineering chimeric antigen receptor (CAR) T cells with logic-gated synthetic Notch (synNotch) receptor circuits can enhance specificity and mitigate on-target/off-tumor toxicity. However, the conventional synNotch system uses two lentiviral vectors encoding the synNotch receptor and inducible CAR, requiring dual transduction and cell sorting, which limits clinical translation. Integrating the synNotch-CAR circuit into a single lentiviral vector could overcome this limitation, yet manufacturing CAR T cells with large transgenes remains challenging, as increasing transgene size drastically reduces lentiviral titers and T cell transduction efficiency. Current production workflows compensate for low transduction efficiency by sorting transduced cells, further impeding clinical translation. Consequently, these constraints have limited the broader development of synNotch-CAR T cell therapies.
METHODS: We engineered a single-vector synNotch (svsNotch) system that integrates all components of the conventional dual-vector circuit into one lentiviral vector to facilitate clinical translation. To overcome the low lentiviral titers and T cell transduction efficiency caused by the large svsNotch transgene, we established an optimized CAR T cell production workflow for effector T cells with large lentiviral transgenes.
RESULTS: Our optimized workflow increased T cell transduction rates by up to 14.8-fold and enabled the production of effector T cells with lentiviral transgenes exceeding the effective packaging capacity limit of 9.2 kb. As a proof of concept, we engineered human epidermal growth factor receptor 2 (HER2)-mesothelin (MSLN) svsNotch (9.2 kb), in which a synNotch receptor targeting HER2 regulates the expression of a second-generation 4-1BBζ CAR against MSLN to enable selective targeting of double-positive HER2+MSLN+ ovarian tumors. In vitro, HER2-MSLN svsNotch T cells demonstrated superior specificity to conventional dual-vector synNotch-CAR T cells, with selective cytotoxicity against HER2+MSLN+ but not HER2koMSLN+ tumor cells. To enable in vivo monitoring, we engineered HER2-MSLN-click beetle green (CBG) svsNotch (10.1 kb) incorporating CBG luciferase. In mouse models using constitutive CAR T cells as controls, HER2-MSLN-CBG svsNotch T cells exhibited minimal cytotoxicity in the absence of HER2 and superior efficacy against HER2lowMSLNhigh and HER2highMSLNhigh tumors.
CONCLUSION: These data establish a framework for engineering logic-gated single-vector immunotherapies and provide an optimized workflow for generating CAR T cells with transgenes that exceed current size limitations.

Keywords:  T-lymphocytes; chimeric antigen receptor - CAR; immune modulatory; immunotherapy; ovarian cancer

DOI:  https://doi.org/10.1136/jitc-2025-012318
Sci Adv. 2026 Jan 09. 12(2): eadz1385

ERα activates NAMPT/IL-33 signaling to enhance beige thermogenesis and metabolic fitness.

Ruoci Hu, Jooman Park, Yanyu Qian, Shaolei Xiong, Ahmad Hamza Elsabbagh, Aditya Chhikara, Huailing Fan, Zuoxiao Shi, Lifeng Liu, Yanhui Li, Zhenyuan Song, Abeer M Mahmoud, Jiwang Chen, Joseph A Baur, Yanlin He, Brian T Layden, Zhenqi Zhou, Pingwen Xu, Sang-Ging Ong, Zilai Wang, Yuwei Jiang.

Beige adipocytes are inducible thermogenic fat cells that emerge within white adipose tissue (WAT) in response to thermogenic stimuli and confer metabolic benefits. However, obesity impairs the generation of beige adipocytes, and the underlying mechanisms remain poorly understood. Here, we show that obesity leads to a loss of adipose progenitor cells (APCs) in WAT, accompanied by reduced estrogen (E2) levels and nicotinamide phosphoribosyltransferase (NAMPT) expression. Supplementation with E2 or nicotinamide mononucleotide (NMN), an NAMPT-derived nicotinamide adenine dinucleotide (NAD+) precursor, restores beige adipogenesis in diet-induced obese mice. Mechanistically, estrogen receptor α (ERα) in APCs is required for beige fat formation by promoting Nampt transcription. We further demonstrate that NAMPT is both necessary and sufficient to drive APC proliferation and differentiation, with interleukin-33 (IL-33) acting downstream to mediate these effects. These findings uncover a critical ERα/NAMPT/IL-33 axis that preserves progenitor function and thermogenic capacity, offering a potential therapeutic strategy to combat obesity-induced beige fat failure and associated metabolic dysfunction.

DOI: https://doi.org/10.1126/sciadv.adz1385