bims-imseme 2026-03-15 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–03–15
twenty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Post-Translational Regulation of CD8+ T Cell Fate and Dysfunction in Tumor Immunity.
Balancing Intrinsic and Extrinsic Factors in CD8+ T Cell Therapy.
Transcriptional programming governs the transition from shared progenitors to divergent CD8+ T cell fates.
β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.
FYN/LCK kinase balance as a metabolic switch orchestrates progenitor exhausted T Cell differentiation in hepatocellular carcinoma.
LIFUS-driven engineered bacteria reprogram immunosuppressive niches via mechano-NOTCH signaling.
Reversing T cell dysfunction in a novel in vitro model of T cell exhaustion reveals differential roles of RASA2.
Overexpression of the transcriptional corepressor Tle1 enhances effector proliferation of CD8+ T cells during acute and chronic viral infections.
Unique phenotypic and T cell receptor characteristics of CD8+ T cells accumulated in the brains of Alzheimer's disease mice.
Contrasting functions of CD73 and adenosine in CD8+ T-cell exhaustion during antitumor immunity.
Auto-inducible expression of chimeric antigen receptor T cells using the NR4A1 promoter.
Communication breakdown: senescent cells in interorgan communication of aging.
Ubiquitin E3 ligase KLHL6 brings exhausted T-cells back into action.
Vitamin B6 modulates CD8+ T cell antitumor responses.
Network Rewiring in the Aging Immune System: From Chronic Inflammation to Age-Related Pathologies.
Inhibition of T cell polyamine metabolism promotes transplant acceptance by modulating cytotoxic CD8+ T cell differentiation.
Single-Cell Profiling of Splenic Immune Ageing and Chronic Stress Adaptations in Mice With Natural Microbiota.
Folate promotes colorectal cancer progression by impairing CD8+ T cell function and recruitment via SLC19A1/p-AKT/NOTCH1 axis and CCL5 downregulation.
Integration of biochemical and physical cues by patrolling CD8+ T cells.
NAD⁺ as a central metabolic hub Regulating the hallmarks of aging: Mechanisms and therapeutic implications.
Predictive biomarkers of response to chimeric antigen receptor (CAR) T-cell therapy for pan-haematologic cancer.
Targeting tumor-infiltrating regulatory T cells based on immunometabolism.

Adv Sci (Weinh). 2026 Mar 12. e74807

Post-Translational Regulation of CD8+ T Cell Fate and Dysfunction in Tumor Immunity.

Zihao Zhou, Xu Chen, Nina Li, Meiyan Zou, Yunfan Lin, Pei Lin, Weiyao Feng, Xinyuan Zhao, Li Cui.

  CD8+ T cells are central executors of antitumor immunity, yet their activation, effector differentiation, and long-term persistence are governed by diverse post-translational modifications (PTMs). These chemical modifications function as rapid and reversible regulators that link antigenic stimulation, metabolic availability, and inflammatory cues to the transcriptional and chromatin programs that define CD8+ T cell fate. Core PTM classes-including phosphorylation, ubiquitination, acetylation, methylation, and glycosylation-precisely tune signaling thresholds, cytotoxic commitment, and memory formation, while emerging metabolism-responsive modifications such as lactylation directly connect nutrient flux to functional fitness. In solid tumors, chronic antigen exposure, hypoxia, nutrient restriction, and lactate accumulation profoundly remodel these modification networks, stabilizing dysfunction-associated states, impairing metabolic flexibility, and diminishing cytotoxic capacity. This review integrates current mechanistic understanding of how major PTM pathways coordinate the lifecycle of CD8+ T cells-from initial activation to effector acquisition, memory establishment, dysfunction, and exhaustion. We further discuss how the tumor microenvironment reprograms PTM landscapes to reinforce dysfunction and promote immune escape. Finally, we highlight the challenges and future directions in deciphering and targeting PTMs in CD8+ T cells. Future efforts to manipulate PTMs hold significant potential to improve cancer immunotherapies by restoring the antitumor efficacy of CD8+ T cells within the tumor microenvironment.

Keywords:  CD8+ T cell; PTMs; TME; metabolic regulation; tumor immunotherapy

DOI:  https://doi.org/10.1002/advs.74807
Immune Netw. 2026 Feb;26(1): e5

Balancing Intrinsic and Extrinsic Factors in CD8+ T Cell Therapy.

Dongwook Lee, Yoontae Lee.

  Persistent Ag exposure in tumors, chronic infections, and autoimmune diseases progressively drive CD8+ T cell dysfunction-a process known as T cell exhaustion. During this process, progenitor exhausted CD8+ T (Tpex) cells represent an early subset with stem cell-like properties and serve as key mediators of immune checkpoint blockade responses. Despite their longevity and proliferative capacity, Tpex cells display limited cytotoxicity. Upon sustained TCR stimulation, they differentiate into exhausted CD8+ T (Tex) cells that express high levels of granzyme B and contribute critically to tumor elimination. Accumulating evidence indicates that Tex cells are functionally heterogeneous, as defined by diverse surface markers and transcriptional programs, and their states are further shaped by tissue- and context-specific cues within the tumor or inflammatory microenvironment. Such extrinsic signals can compromise CD8+ T cell function and limit the efficacy of anti-PD-1 therapy. A comprehensive understanding of this heterogeneity, integrating both intrinsic transcriptional regulation and extrinsic modulatory signals, is crucial for developing more effective immunotherapeutic strategies. Finally, T cell exhaustion should not be viewed solely as a pathological endpoint but also as an adaptive mechanism that restrains immunopathology, underscoring its context-dependent roles across cancer, infection, and autoimmunity.

Keywords:  Autoimmunity; Cytotoxicity, immunologic; Immunotherapy; Population heterogeneity; T-cell exhaustion; Tumor microenvironment

DOI:  https://doi.org/10.4110/in.2026.26.e5
Immunol Cell Biol. 2026 Mar 11.

Transcriptional programming governs the transition from shared progenitors to divergent CD8+ T cell fates.

M Zeeshan Chaudhry, Gabrielle T Belz.

  Research in 2025 demonstrated that memory and exhausted CD8+ T cell lineages arise from shared TCF1+ progenitors and that fate divergence is actively enforced by transcriptional programs rather than fixed at priming. Multi-state regulators such as KLF2 and GFI1 preserve stemness, restrain exhaustion, and calibrate differentiation under acute and chronic antigenic stress.

Keywords:  GFI1; KLF2; T cell exhaustion; T cell memory

DOI:  https://doi.org/10.1111/imcb.70101
Cell. 2026 Mar 06. pii: S0092-8674(26)00169-8. [Epub ahead of print]

β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.

Shan Liu, Puneeth Guruprasad, Ranjani Ramasubramanian, Bhoomi Madhu, Luca Paruzzo, Kecheng Han, Andre Kelly, Alexander Shestov, He N Xu, Alberto Carturan, Chaoting Zhou, Kevin R Amses, Amichay Afriat, Lev Litichevskiy, Jason Lin, Ezra Dubowitz, Neil Tangal, Jing Zhang, Alana McSween, Melody Tan, Federico Stella, Andrew Lee, Siena Nason, Xianxin Hua, Michael Schneider, Madeleine Sleeman, Yunlin Zhang, Giulia Gabrielli, Ziqi Yang, Raymone Pajarillo, Ruchi Patel, Guido Ghilardi, Vrutti Patel, Akshita Joshi, Shunzhou Jiang, Yanqing Jiang, Patrizia Porazzi, Julia C Tchou, Brian Keith, Mingyao Li, Elise Chong, Stephen J Schuster, Michael Milone, Joshua Rabinowitz, Roddy S O'Connor, Christoph A Thaiss, Maayan Levy, Marco Ruella.

  The influence of lifestyle factors, such as diet, on the effectiveness of T cell-mediated cancer immunotherapies remains unclear. Here, we demonstrate that the ketogenic diet (KD)-induced ketone metabolite β-hydroxybutyrate (BHB) augments chimeric antigen receptor (CAR) T cell function across multiple preclinical cancer models. Mechanistically, BHB supports the tricarboxylic acid (TCA) cycle in CAR T cells, driving oxidative phosphorylation and energy generation. This metabolic enhancement is associated with CAR T cell proliferation and cytokine production, thereby leading to superior tumor control. Furthermore, BHB induces global transcriptional and epigenetic reprogramming in activated CAR T cells, which promotes an enhanced effector and metabolic profile. Lastly, in a prospective cohort of healthy volunteers, administration of BHB enhanced peripheral T cell oxygen consumption, mitochondrial membrane potential, and ATP production. Our results suggest that metabolite intervention via BHB supplementation is a promising, readily implementable strategy to improve adoptive T cell function against various cancers.

Keywords:  CAR T cell; cancer therapy; ketogenic diet; metabolism; oxidative phosphorylation; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.cell.2026.02.004
Hepatology. 2026 Mar 11.

FYN/LCK kinase balance as a metabolic switch orchestrates progenitor exhausted T Cell differentiation in hepatocellular carcinoma.

Junyu Wu, Zhuofeng Jiang, Qiucheng Li, Chien-Shan Cheng, Yau-Tuen Chan, Ranna Yeerken, Junbang Chen, Pengde Lu, Zixin Feng, Hongchao Yuan, Lin Xu, Zhiqiang Meng, Yibin Feng, Hor-Yue Tan, Ning Wang.

   BACKGROUND AND AIMS: Immune checkpoint blockade (ICB) shows therapeutic promise in hepatocellular carcinoma (HCC) but is associated with suboptimal responses in patients. Progenitor exhausted T (Tpex) cells are key responders to ICB, but the regulatory mechanisms regarding Tpex maintenance in HCC remain elusive.
APPROACH AND RESULTS: Through an integrated analysis of HCC single-cell RNA-sequencing datasets, we constructed an exhausted CD8+ T cell atlas and identified FYN as a marker of Tpex cells in ICB responders. FYN deficiency in CD8+ T cells induced LCK hyperactivation, which drove terminal exhaustion under high-affinity antigen stimulation. Mechanistically, LCK hyperactivation disrupted metabolic homeostasis by triggering excessive glycolysis and impairing mitochondrial function in Tpex cells. Conversely, LCK inhibition elevated compensatory FYN activity, restored mitochondrial fitness and preserved Tpex cell stemness. In preclinical HCC models, transient LCK inhibition during T cell expansion enhanced adoptive cell therapy efficacy by increasing Tpex cell persistence and stemness. Besides, preemptive low-dose LCK inhibition prior to anti-PD1 therapy expanded the Tpex cell pool, reduced terminal exhaustion, and improved therapeutic outcomes.
CONCLUSIONS: This study establishes the balance between SRC kinases FYN and LCK as a critical regulator of the terminal exhaustion of Tpex cell through metabolic reprogramming. The finding suggests that modulating the FYN/LCK kinase balance is a promising strategy to overcome immunotherapy resistance in HCC.

Keywords:  Adoptive cell transfer; CD8 T cells; SRC kinases; T cell exhaustion; immune checkpoint blockade; metabolic reprogramming

DOI:  https://doi.org/10.1097/HEP.0000000000001740
Cell Rep Med. 2026 Mar 09. pii: S2666-3791(26)00075-3. [Epub ahead of print] 102658

LIFUS-driven engineered bacteria reprogram immunosuppressive niches via mechano-NOTCH signaling.

Lizhou Lin, Xiao Li, Wenyun Guo, Jirong Xie, Xiaolong Li, Xin Guan, Chongke Zhao, HaoHao Yin, Huixiong Xu.

  Solid tumors impose coupled stromal and immunologic barriers that limit T cell infiltration and function. Here, we engineer Salmonella VNP20009 to express gas vesicles (GVs), creating an intratumoral cavitation source that converts low-intensity focused ultrasound (LIFUS) into localized mechanical forces. LIFUS-activated GVs remodel the tumor microenvironment by reducing cancer-associated fibroblast (CAF) abundance, decompressing the matrix, and selectively disrupting CAF-CD8+ T cell communication via a mechanosensitive Notch1-Jagged1 axis. Single-cell RNA sequencing reveals a redistribution of CD8+ T cell states, characterized by enrichment of cytotoxic effector populations and attenuation of NOTCH signaling in memory-associated cells. These biomechanical changes enhance intratumoral CD8+ T cell infiltration and restore effector cytokine production. Leveraging this mechanism, we develop a mechano-priming approach for adoptive T cell therapies. Pre-conditioning with LIFUS-driven GVs improves CD8+ T cell cytotoxicity, strengthens tumor cell adhesion, reduces exhaustion signatures, and achieves durable tumor control and extended survival in orthotopic and metastatic models.

Keywords:  NOTCH pathway; immunotherapy; mechanotransduction; tumor microenvironment; ultrasound

DOI:  https://doi.org/10.1016/j.xcrm.2026.102658
Front Immunol. 2026 ;17 1509926

Reversing T cell dysfunction in a novel in vitro model of T cell exhaustion reveals differential roles of RASA2.

Hilal Saraç, Rachael Nicholson, Rebecca N Graham, Meera Augustus, Raha Taghavi, Dympna J Connolly, Lindsay Lim, Sofia Lourenco.

   Introduction: T cell exhaustion driven by chronic antigen stimulation limits durable responses to cancer immunotherapy. Using repeated soluble anti-CD3/anti-CD28 stimulation, we established an in vitro system that recapitulates hallmark exhaustion features in human CD8+ and CD4+ T cells, including increased PD-1+Tim-3+ subsets and loss of IL-2, TNF-α and IFN-γ secretion. We used our platform to explore the role of RASA2 in CD4+ versus CD8+ T cell exhaustion and assess the feasibility of reversing established exhaustion in T cells.
Methods: Primary human T cells underwent six rounds of chronic stimulation to generate exhausted T cells (Tex), while single-stimulated controls (Ts) were rested in IL-2 media. Exhaustion states were assessed by flow cytometry, cytokine profiling, spectral flow cytometry, and scRNA-seq with pseudotime analysis, across timepoints, resting and activation along the exhaustion protocol. CRISPR-Cas9 RNP editing targeting RASA2 was performed either before exhaustion ("blocking") or post exhaustion directly in in vitro generated exhausted T cells ("reversal") across both CD8+ and CD4+ T cells.
Results: Chronic stimulation induced robust dysfunction marked by elevated PD-1+Tim-3+ cells and diminished effector cytokines in both compartments. RASA2 depletion before exhaustion enhanced cytokine and granzyme secretion without altering inhibitory receptor expression. Notably, direct editing of exhausted T cells achieved ~65% RASA2 loss and restored cytokine and granzyme secretion, with CD4+ Tex exhibiting greater functional plasticity than CD8+ Tex.
Discussion: This work provides the first demonstration of CRISPR editing directly in in vitro generated human exhausted T cells, revealing distinct roles for RASA2 across CD4+ and CD8+ compartments. This platform enables mechanistic dissection of T cell exhaustion biology with increased throughput and physiological relevance, ultimately supporting the development of novel strategies to overcome cancer immunotherapy resistance.

Keywords:  CD4+; CRISPR–Cas9 RNP editing; RASA2; T cell exhaustion; dysfunction reversal; scRNA‑seq; spectral flow cytometry

DOI:  https://doi.org/10.3389/fimmu.2026.1509926
Int Immunol. 2026 Mar 11. pii: dxag001. [Epub ahead of print]

Overexpression of the transcriptional corepressor Tle1 enhances effector proliferation of CD8+ T cells during acute and chronic viral infections.

Ryotaro Shiga, Sotaro Fujisawa, Yamato Tanabe, Junko Kurachi, Miki Koura, Toshikatsu Tamai, Makoto Kurachi.

  The transcriptional corepressor Tle (transducin-like enhancer of split) proteins interact with transcription factors such as TCF-1 and Runx3 to regulate transcriptional programmes during cellular development and differentiation; however, their roles in CD8+ T cell differentiation, particularly under conditions of chronic antigen stimulation, remain poorly defined. Here, we demonstrated that overexpression of Tle1, Tle3, and Tle4 improves the proliferation of antigen-specific effector CD8+ T cells during both acute and chronic viral infections. Notably, overexpression of Tle3 and Tle4, but not Tle1, augmented secondary responses of memory CD8+ T cells in the context of acute viral infection. Tle1-overexpressing CD8+ T cells displayed enhanced TCR signal strength, accompanied by elevated expression of immunoinhibitory receptors such as PD-1 and LAG-3. Transcriptome analyses and genome-wide binding profiles suggested that Tle1 and Tle3 cooperate with multiple transcription factors, including members of the Ets, AP-1, and Runx families, to drive expression of genes involved in the activation and maintenance of antigen-specific CD8+ T cell responses. Notably, Tle1 overexpression improves cytotoxic T lymphocyte (CTL) responses to PD-1/PD-L1 blockade during chronic viral infection. Tle1 was found to enhance TCR signalling and the expression of immunoinhibitory receptors through repression of TCF-1, whereas its effect on effector CD8+ T cell proliferation occurred independently of TCF-1. These findings revealed the regulatory roles of Tle proteins in orchestrating transcription factor networks that govern CD8+ T cell differentiation during viral infections.

Keywords:  CD8+ T cell differentiation; LCMV; Tle corepressor

DOI:  https://doi.org/10.1093/intimm/dxag001
Sci Rep. 2026 Mar 07.

Unique phenotypic and T cell receptor characteristics of CD8+ T cells accumulated in the brains of Alzheimer's disease mice.

Wang Zhihuan, Emi Furusawa-Nishii, Sachiko Miyake.



Keywords:  Aging; Alzheimer’s disease; C-X-C chemokine receptor type 6; CD8+ tissue-resident memory T cells

DOI:  https://doi.org/10.1038/s41598-026-38351-8
Oncoimmunology. 2026 Dec 31. 15(1): 2642458

Contrasting functions of CD73 and adenosine in CD8+ T-cell exhaustion during antitumor immunity.

Juan Saavedra-Almarza, Solange Gouët, Felipe Malgue, Catalina Bascuñan, Andrés Hernández-Oliveras, Joaquín De la Rosa, Javiera Reyes-Alvarez, Camilo Villaman, José Corrales-Bermúdez, Justine Castañeda, Moira García-Gómez, Alberto J M Martin, Álvaro Lladser, Mario Rosemblatt, María Rosa Bono, Daniela Sauma.

  T-cell exhaustion is a state of functional decline in T cells, driven by chronic antigen exposure and inhibitory signals within the tumor microenvironment. Exhausted CD8+ T cells (Tex) derive from precursor exhausted T cells (Tpex), a self-renewing population responsible for the proliferative burst in anti-PD-1 therapies. Exhausted T cells are exposed to adenosine in the tumor, yet the role of the CD73/adenosine axis and Tpex/Tex differentiation remains unclear. Using an in vitro model for CD8+ T-cell exhaustion, we found that CD73 expression increased during Tpex formation and that its expression was negatively correlated with Tex generation. CD73-deficient OT-I cells (OT-I/CD73KO) showed impaired activation and reduced progression to Tex. Moreover, we demonstrated that CD73 promotes transcriptional expression of the adenosine receptor A2A (A2AR). RNA-seq analysis of exhausted OT-I/CD73KO cells revealed a more stem-like transcriptomic profile and enrichment in genes associated with the immune response compared to their OT-I counterparts. In vivo, the cotransfer of naïve OT-I/CD73KO and OT-I antigen-specific CD8⁺ T cells into tumor-bearing mice resulted in increased Tpex frequency and numbers among OT-I/CD73KO cells in tumors. Conversely, in vitro exhaustion in the presence of A2AR agonists decreased Tex frequency and activation/exhaustion markers, while increasing CD73 and CD62L, which are markers associated with stemness. Supporting this, A2AR blockade with SYN115 in tumor-bearing mice reduced Tpex markers and increased Tex differentiation. Altogether, our data suggest that CD73 promotes Tpex-to-Tex differentiation, whereas adenosine A2AR signaling supports Tpex maintenance in the tumor microenvironment.

Keywords:  A2AR signaling; Adenosine; CD73; Ecto-5′; NT; Exhausted CD8+ T cells; melanoma

DOI:  https://doi.org/10.1080/2162402X.2026.2642458
Immunol Cell Biol. 2026 Mar 08.

Auto-inducible expression of chimeric antigen receptor T cells using the NR4A1 promoter.

Samuel Wj Smith-Bell, Joshua C Halpin, Phillip K Darcy, Thiloma Liyanage, Lachlan J Dobson, Alexander D McLellan.

  Chimeric antigen receptor (CAR) T cell therapies have shown remarkable efficacy in hematological malignancies, yet translation to solid tumors has been hindered by immunosuppressive tumor microenvironments, reduced T cell persistence and on-target/off-tumor toxicities. Constitutive CAR expression, typically driven by strong promoters such as EF1α, promotes tonic signaling, receptor clustering and antigen-independent activation, contributing to T cell exhaustion and adverse events. Inducible promoter systems have been proposed to improve control over CAR expression. NR4A1, a transcription factor (TF) activated during early T cell receptor (TCR) signaling, governs pathways central to T cell activation and dysfunction, making its promoter an attractive candidate for conditional CAR regulation. We compared constitutive (EF1α), synthetic inducible (6NFAT-NFκB and 2NFAT-2NurRE) and NR4A1 promoters to drive expression of a second-generation FRP5-CAR. NR4A1-driven CARs demonstrated low basal expression that was rapidly induced upon antigen encounter, reaching levels equivalent to EF1α-driven CARs while showing minimal antigen-independent signaling. Functionally, NR4A1-driven CARs mediated potent tumor lysis, preserved a less exhausted (PD-1low and TIM-3low) and more memory-like phenotype (CD62Lhigh and CD45RAhigh), and sustained robust antitumor responses in vitro and in vivo. These findings establish the NR4A1 promoter as a native, activation-inducible system to fine-tune CAR expression, while maintaining therapeutic efficacy comparable to constitutively expressed CAR T cells. This strategy provides a promising framework for advancing CAR T cell therapies against solid tumors.

Keywords:  CAR T cells; PD1; T cell exhaustion; inducible promoters

DOI:  https://doi.org/10.1111/imcb.70095
Trends Endocrinol Metab. 2026 Mar 10. pii: S1043-2760(26)00037-8. [Epub ahead of print]

Communication breakdown: senescent cells in interorgan communication of aging.

Rituparna Ghosh, Shweta S Dipali, Gabriela Desdín-Míco, Matthew J Yousefzadeh.

  Cellular senescence is a complex cell fate characterized by stable cell cycle arrest and other heterogeneous changes. Senescent cells play a causal role in aging, although the underlying mechanisms remain under active investigation. In this opinion article, we propose that senescent cells can act as key mediators of interorgan communication of aging. Recent work defines multifaceted mechanisms, including the production of senescence-associated secretory phenotype factors that act to propagate senescence signals to nearby and distant cells, as well as age-related alterations in immune function that drive chronic inflammation, known as 'inflammaging'. Further investigation of these mechanisms could yield improved strategies to target senescent cells and mitigate their effects on systemic aging via interorgan communication of aging.

Keywords:  cellular senescence; immunosenescence; inflammaging; inflammation; interorgan aging

DOI:  https://doi.org/10.1016/j.tem.2026.02.002
Immun Inflamm. 2026 ;2(1): 16

Ubiquitin E3 ligase KLHL6 brings exhausted T-cells back into action.

Zhuoyao Chen, Alex N Bullock, Benedikt M Kessler.

  Persistent antigen stimulation drives CD8⁺ T-cell exhaustion in cancer and chronic infection, limiting immunotherapy efficacy. Two recent studies identify the ubiquitin E3 ligase Kelch-like protein KLHL6 as a key suppressor of T-cell exhaustion. KLHL6 is maintained in progenitor and memory-like T cells but lost upon chronic TCR signaling through PI3K-AKT-mediated inhibition of FOXO1. By targeting TOX and mitochondrial regulators, such as PGAM5, KLHL6 preserves T-cell function, and its restoration rescues antitumor immunity. This discovery reveals the relevance of KLHL6 mediated ubiquitylation not only in B-lymphocytes, but also in T-cells, thereby highlighting a promising new avenue for immunotherapeutic intervention.

Keywords:  CD8+ lymphocytes; E3 ligase; Kelch-like protein; T-cell exhaustion; Ubiquitin

DOI:  https://doi.org/10.1007/s44466-026-00032-6
Dev Cell. 2026 Mar 11. pii: S1534-5807(26)00080-8. [Epub ahead of print]61(3): 468-469

Vitamin B6 modulates CD8+ T cell antitumor responses.

Iosifina P Foskolou.

In this issue of Developmental Cell, Wu et al. report that the active form of vitamin B6, pyridoxal phosphate (PLP), enhances CD8+ T cell-dependent tumor clearance. Mechanistically, PLP maintains CD8+ T cells in a stemness-like state by inhibiting the nuclear translocation of BACH2. Here, we discuss these findings and their implications for cancer immunotherapy.

DOI: https://doi.org/10.1016/j.devcel.2026.02.015
Cells. 2026 Feb 27. pii: 414. [Epub ahead of print]15(5):

Network Rewiring in the Aging Immune System: From Chronic Inflammation to Age-Related Pathologies.

Ludmila Müller, Svetlana Di Benedetto.

  Aging is accompanied by profound alterations in immune function that collectively drive increased susceptibility to infection, reduced vaccine efficacy, impaired tissue repair, and heightened risk of age-related diseases (ARDs). These alterations are characterized by the coexistence of immunosenescence and inflammaging. Rather than reflecting isolated cellular defects, immune aging emerges as a systems-level reprogramming of immune networks that disrupts the initiation, resolution, and regenerative phases of inflammatory responses. In particular, aging is associated with impaired resolution of inflammation, defective efferocytosis, reduced responsiveness to pro-resolving signals, and diminished regenerative capacity, leading to persistent inflammatory milieus and tissue damage. This review summarizes recent advances in the mechanisms underlying immune dysfunction in aging, with a focus on how chronic inflammation, failed resolution, and defective repair reinforce one another. We discuss how alterations in innate and adaptive immunity, immunometabolism, cellular senescence, and immune-tissue interactions drive inflammaging and contribute to major ARDs, including cancer, neurodegenerative, and cardiometabolic diseases. Finally, we highlight emerging therapeutic strategies aimed at restoring immune balance and resolution. By adopting a systems-level and network-based perspective, this review underscores immune aging as a modifiable driver of ARDs and identifies key knowledge gaps and future directions toward interventions that promote healthy aging and extended healthspan.

Keywords:  age-related diseases; immunosenescence; impaired resolution of inflammation; inflammaging; pro-resolving lipid mediators; systems-level and network-based perspective; therapy

DOI:  https://doi.org/10.3390/cells15050414
Am J Transplant. 2026 Mar 09. pii: S1600-6135(26)00124-3. [Epub ahead of print]

Inhibition of T cell polyamine metabolism promotes transplant acceptance by modulating cytotoxic CD8+ T cell differentiation.

Renjie Tang, Yuan Chang, Yuqi An, Dan Shan, Shen Song, Kai Xing, Peiyuan Li, Hang Zhang, Xiumeng Hua, Xiao Chen, Ningning Zhang, Shengshou Hu, Jiangping Song.

  Polyamines, particularly spermidine, are well-documented for their cardiovascular protective, antitumor, and longevity-promoting properties. However, their role in heart transplantation, and specifically the contribution of T-cell polyamine metabolism to transplant acceptance, remains undefined. In this study, we integrated preclinical and clinical studies to address this gap. We found that polyamine metabolism was significantly upregulated in T cells during acute rejection (AR) in both murine allografts and human AR samples. Critically, conditional inhibition of polyamine metabolism in T cells completely prevents AR and promotes long-term graft survival. Mechanistically, we found that polyamine metabolism is crucial for the differentiation of cytotoxic CD8+ T cells. Further, this regulatory effect was mediated by polyamine-dependent hypusination of eukaryotic initiation factor 5A (eIF5A), with inhibition of T cell eIF5A hypusination recapitulating the anti-AR effects of polyamine blockade. Our study identifies T cell polyamine metabolism as a critical regulator of cytotoxic CD8+ T cell differentiation and AR in heart transplantation. Targeting this pathway holds promise as a novel therapeutic strategy for treating AR.

Keywords:  Acute rejection; Heart transplantation; Odc1; Polyamine metabolism; T cell; eIF5A hypusination

DOI:  https://doi.org/10.1016/j.ajt.2026.02.038
Eur J Immunol. 2026 Mar;56(3): e70170

Single-Cell Profiling of Splenic Immune Ageing and Chronic Stress Adaptations in Mice With Natural Microbiota.

Chinna Susan Philip, Igor Filippov, Uku Haljasorg, Pärt Peterson.

  Immune ageing impairs adaptive and innate responses, yet the spleen remains underexplored by cross-cohort single-cell studies. We profiled splenocytes from young, old and chronically stressed old mice with natural microbiota using single-cell RNA sequencing. Ageing was characterised by reduced lymphocyte competence and elevated stress responses. Within Gzmk+ CD8+ T cells, young mice were enriched for Gzmk-high cells, whereas in old mice, both Gzmk-high and Gzmk-low cells showed greater heterogeneity and functional alterations: exhaustion in Gzmk-high and inflammation in Gzmk-low cells. Natural killer (NK) cells and macrophages exhibited reduced cytotoxic potential and sustained pro-inflammatory polarisation, respectively. Chronic stress caused modest compositional shifts that partially counteracted age-related changes. Furthermore, we integrated our dataset with six published datasets to build a comprehensive atlas with > 272,000 splenocytes. Atlas-level annotation showed reproducible compositional shifts across datasets. Conserved ageing signatures included loss of NK effector genes (Zeb2, Prf1), decline of naïve T quiescence (Lef1, Il7r) with stress induction (Rbm3, Socs3), gain of survival/pro-inflammatory/exhaustion genes (Bcl2, S100a6, Ccl5, Lag3) in effector T cells, and altered differentiation and regulation (Zbtb32, Zbtb20, Zfp318, Ighd, Cr2) in B cells. Our results define conserved features of splenic immunosenescence and provide an atlas for dissecting splenic immune alterations.

Keywords:  T cells; ageing; chronic stress; spleen; transcriptomic

DOI:  https://doi.org/10.1002/eji.70170
J Transl Med. 2026 Mar 13.

Folate promotes colorectal cancer progression by impairing CD8+ T cell function and recruitment via SLC19A1/p-AKT/NOTCH1 axis and CCL5 downregulation.

Shunjie Qing, Yunyan Ling, Yingjie Lai, Yating Hu, Yi Zhong, Yuechen Liu, Xiang Liu, Yuan Fang, Junying Qian, Haijun Deng, Yifeng Peng, Dehua Wu, Zhiyong Shen.

   BACKGROUND: Dietary factors have been recognised as contributors to the etiology of colorectal cancer (CRC). Folate is a micronutrient of critical importance to human health, frequently utilized as a dietary supplement. Previous clinical evidence suggested that folate intake is associated with an increased risk of CRC. However, the underlying mechanisms remain unclear. Here, we report that folate supplementation significantly promotes CRC growth and is associated with functional exhaustion of cytotoxic CD8+ T cell to enhance immune evasion.
METHODS: Using subcutaneous and orthotopic colorectal cancer mouse models, we investigated the impact of folate on CRC progression. Flow cytometry, immunohistochemistry, immunofluorescence, Transwell assays, RNA sequencing, and ChIP-qPCR were employed to elucidate the role and underlying mechanisms of folate in modulating CD8+ T cell function and recruitment within the tumor. By integrating dietary folate restriction with PD-1 monoclonal antibody therapy in subcutaneous tumor models, we further explored its effects in a preclinical setting.
RESULTS: Our study indicates that folate directly impairs cytotoxic CD8+ T cell function and promotes immune escape, thereby accelerating colorectal cancer progression. Mechanistically, folate enhances the expression of SLC19A1, which encodes the folate transporter RFC1, by promoting AKT phosphorylation. Elevated AKT phosphorylation activates the downstream NOTCH1 signaling pathway, leading to a T cell exhaustion phenotype. Meanwhile, folate in the tumor microenvironment suppresses PBX3 expression in CRC cells, thereby reducing CCL5 transcription and impeding CD8+ T cell recruitment. Furthermore, in vivo dietary folate restriction enhances tumor control and synergizes with anti-PD-1 immunotherapy in CRC.
CONCLUSIONS: This preclinical study suggests that folate may facilitate CRC progression and immune evasion by impairing CD8+ T cell recruitment and anti-tumor activity. These findings represent a proof-of-concept in mouse immunometabolism offering insights into potential mechanisms underlying folate-driven CRC progression and immune suppression. Broader implications for nutritional interventions or immunotherapy in patients remain speculative at this preclinical stage and would require further clinical investigation.

Keywords:  CD8+ T cell exhaustion; Colorectal cancer; Folate; Immunotherapy

DOI:  https://doi.org/10.1186/s12967-026-07993-7
Trends Immunol. 2026 Mar 07. pii: S1471-4906(26)00035-9. [Epub ahead of print]

Integration of biochemical and physical cues by patrolling CD8+ T cells.

Jens V Stein, Heidi E L Lischer, Clara V I Palou, Aditya Seth, Rémy Bruggmann.

CD8+ T cell migration is central to host defense, enabling clonal selection, tissue infiltration, and elimination of infected cells. While chemokines guide these cells by activating Rac for F-actin polymerization, recent studies reveal a complementary mechanism through Rho activation. This pathway relies on tissue confinement, which deforms the nucleus, activates the actomyosin network, and allows CD8+ T cells to use physical cues for surveillance without external signals. In this review article, we explore how chemokine- and mechanosensing-dependent pathways guide CD8+ T cell surveillance and introduce a 'front-' versus 'rear-driven' motility model to illustrate their integration for effective tissue monitoring. Ultimately, the interplay of biochemical and physical cues ensures tissue-specific protection by T cells during homeostasis and inflammation.

DOI: https://doi.org/10.1016/j.it.2026.02.004
Mech Ageing Dev. 2026 Mar 09. pii: S0047-6374(26)00026-6. [Epub ahead of print]231 112174

NAD⁺ as a central metabolic hub Regulating the hallmarks of aging: Mechanisms and therapeutic implications.

Zerong Pei, Fengni Liang, Xuemei Wang, Hui Li.

  The increasing global burden of age-related diseases necessitates interventions that target the unified biological processes of aging, as outlined by the expanding framework of fourteen interconnected hallmarks. This review establishes nicotinamide adenine dinucleotide (NAD⁺) as the central metabolic hub that coordinately regulates this entire network. We systematically elucidate the bidirectional mechanistic links between NAD⁺ metabolism and each hallmark, demonstrating how its age-related decline-driven by impaired biosynthesis and heightened consumption-propagates dysfunction across genomic, epigenetic, mitochondrial, proteostatic, and communicative processes. A large body of evidence supports that NAD⁺ can counter functional decline in models of neurodegenerative diseases, cardiometabolic diseases, and musculoskeletal aging However, a critical synthesis of evidence reveals a paradoxical, context-dependent role for NAD⁺, particularly in oncology, where it can sustain the pro-tumorigenic senescence-associated secretory phenotype (SASP) and fuel established cancers. This duality, along with tissue-specific metabolic nuances, underscores the fundamental limitation of indiscriminate "blind supplementation." Consequently, we advocate for a necessary paradigm shift towards "precision NAD⁺ modulation." Building on the integrated mechanistic analysis, we critically examine the therapeutic implications and challenges across major age-related diseases. Looking ahead, we propose that advancing the field requires embracing a "NAD⁺ systems biology" perspective. Design next-generation interventions that precisely balance tissue-specific NAD⁺ synthesis and consumption. This paradigm is essential for translating the promise of NAD⁺ biology into safe and effective strategies for extending human healthspan.

Keywords:  Aging hallmarks; Healthspan; Metabolic regulation; NAD⁺; Precision geroscience; Sirtuins

DOI:  https://doi.org/10.1016/j.mad.2026.112174
Nat Biomed Eng. 2026 Mar 09.

Predictive biomarkers of response to chimeric antigen receptor (CAR) T-cell therapy for pan-haematologic cancer.

Gregory M Chen, Ankita Jain, David T Gering, Javier Satulovsky, Sarbani Datta, Peng Lai, Jayashree Karar, Vanessa E Gonzalez, Kathleen Alexander, Anne Chew, Julie K Jadlowsky, Marco Ruella, Luca Paruzzo, Kevin R Amses, Andrew J Rech, Edward A Stadtmauer, Noelle V Frey, Elizabeth O Hexner, David L Porter, Adam D Cohen, Saar I Gill, Alfred L Garfall, Stephen J Schuster, Kelvin C Mo, Samantha I Liang, Marko Spasic, Bruce L Levine, Don L Siegel, Angel Ramírez-Fernández, Christopher R Cabanski, EnJun Yang, Crystal L Mackall, Frederic D Bushman, Zinaida Good, E John Wherry, Carl H June, Joseph A Fraietta.

Chimeric antigen receptor (CAR) T-cell therapy holds great promise for patients with cancer, and the identification of predictive biomarkers is crucial in finding new ways to guide therapy. Major challenges to the application of informatics and machine learning in CAR T-cell therapy include limited sample sizes and non-uniformity in data generation across cancer indications and trials. Here we took a global, pan-haematologic cancer approach, analysing 256 patients across 5 cancer types and 13 clinical trials. We generated data using a framework that included pre-infusion clinical features, over 2 million apheresis T cells analysed by flow cytometry using 17 unique markers, ex vivo T-cell expansion during CAR T-cell manufacture, more than 90,000 measurements of 30 serum markers and serial tracking of circulating CAR T cells using qPCR. From this data resource, we demonstrate the potential of pan-cancer predictive biomarkers that capture generalizable characteristics of treatment response and non-response in CAR T-cell therapy.

DOI: https://doi.org/10.1038/s41551-026-01633-7
Cancer Biol Med. 2026 Mar 10. pii: j.issn.2095-3941.2025.0645. [Epub ahead of print]23(2):

Targeting tumor-infiltrating regulatory T cells based on immunometabolism.

Na Li, Dexue Tian.

  The immune checkpoint blockade (ICB) approach in cancer therapy involves the disruption of immune checkpoint inhibitory signals on tumor-specific CD8+ T cells, thereby reinstating the immune activity of CD8+ T cells and yielding therapeutic efficacy. However, due to the co-expression of immune checkpoint molecules, such as CTLA-4 and PD-1 on tumor-infiltrating Tregs (TI-Tregs) and conventional T cells (Tconvs), immune checkpoint inhibitors (ICIs) inadvertently amplify the immunosuppressive activity of Tregs while targeting CD8+ T cells, which contributes to the failure of immune therapy. Conventional strategies targeting Tregs, including ICI/conventional kinase and chemokine/chemokine receptor blockade, generally induce systemic Treg depletion, which triggers autoimmune diseases. Thus, achieving high selectivity and specificity in targeting TI-Tregs is of paramount importance in mitigating adverse immunologic reactions. Targeting metabolism-based TI-Tregs has been shown to enhance target precision, providing potential for the development of adjunctive immunotherapeutic strategies. This article explores the reciprocal interaction between TI-Tregs and the tumor microenvironment (TME), elucidating metabolic reprogramming, while envisioning plausible high-selectivity targets for TI-Tregs without compromising systemic immune homeostasis and immune reactivity of effector T cells.

Keywords:  CD8+ T cells; Tumor-infiltrating regulatory T cells; immune checkpoint inhibitors; immunometabolism; tumor microenvironment

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0645