bims-imseme 2026-07-19 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–07–19
37 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Targeting DNMT1 augments anti-tumor CD8⁺ T cell function.
MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion.
Ablating Satb1 reprograms the differentiation trajectory of exhausted CD8+ T subsets to enhance antitumor immunity.
NOSIP overexpression promotes long-term persistence of CD8+ T cells during chronic infection.
IL-7-glucose-Aiolos axis orchestrates pathogenic CD8+ T cell function in spondyloarthritis.
Glucose Metabolism in Immune Regulation: From Mechanisms to Therapeutic Opportunities.
Sleeping Beauty mutagenesis identifies BACH2 and other regulators of CD8+ T-cell exhaustion, persistence in vivo, and CAR-T cell function under tumor-associated chronic antigen stimulation.
CXCR6 marks polyfunctional effector CD4 T cells required for anti- Chlamydia immunity in the female reproductive tract.
Single-Cell Pan-Cancer Atlas Reveals GPR171 as a Candidate Marker of CD8+ T-Cell Dysfunction.
Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate.
PSGL-1 blockade delays relapse to BRAF/MEK inhibition in cutaneous melanoma.
CD4+ T cells persist with their Eomes.
Expression of the switch receptor PD1/IL15Rβ in MSLN-CAR-T cells overcomes PD1/PDL1 signaling in solid tumors.
Augmenting CAR T cell functionality and metabolism through CD39 downtuning.
Immune cell lncRNAs reprogram the tumor microenvironment.
CD4+ T cells play distinct roles during the priming versus effector phases of immune checkpoint therapy-dependent tumor elimination by CD8+ T cells.
Confined T cell migration controls programmed cell death 1 expression.
The Relationship Between Neutrophil Extracellular Traps and CD8+ T Lymphocytes in Cancer: A Comprehensive Review of Current Data.
Disrupting fumarylacetoacetate hydrolase by stratified nanoplatforms orchestrates metabolic-immune reprogramming and prevents post-ablation HCC relapse.
NK-like and networked CD8 + T cell immunity mediates exceptional HIV control.
Intrinsic T-cell programming and immune spatial organization govern sex-biased tuberculosis immunity.
Reversible control of CAR T cells through PROTAC compound targeting bromodomain mutant.
Differential NAD + availability may drive asymmetric SIRT7 activity in tumor and immune cells.
Distinct macrophage and T cell programs shape pancreatic inflammation during metabolic stress and aging.
TP53 mutation-biased CD8+ T cell exhaustion drives lethal outcome and therapy resistance in urothelial carcinoma.
A targetable micropeptide reprograms macrophages to suppress T cell anti-tumor immunity.
From barrier to trigger: leveraging tumor hypoxia for precise control of CAR-T cell activity.
Perspective: Hormones and immune development: bidirectional regulation between thyroid hormones and the immune system.
Medium chain fatty acid sensing receptor GPR84 limits antitumor immunity mediated by CD4 T cells in mice.
A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
What Do We Know About Immune System Aging from Human and Animal Studies?
Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
Immuno-metabolic reprogramming in pulmonary fibrosis: Emerging therapeutic targets beyond inflammation.
Ammonia metabolic reprogramming in the tumor microenvironment: emergence of an immunosuppressive niche.
NAFLD-associated immune remodeling in colorectal cancer liver metastasis: mechanisms and implications for immunotherapy.
The mitochondrial logic of inflammaging: how energy imbalance drives fibroblast SASP and tissue-specific aging.
The SIRT5-SUCLG2 desuccinylation axis delays ovarian aging via a mitochondrial-epigenetic regulatory mechanism.

bioRxiv. 2026 Jul 06. pii: 2026.07.03.736412. [Epub ahead of print]

Targeting DNMT1 augments anti-tumor CD8⁺ T cell function.

Maya G Deshmukh, Danielle Sohai, Kamal Obbad, Koonam Park, Simon Milette, Peili Gu, Henna S Nam, Andrew J Daniels, Krasimir A Spasov, Michael Hurwitz, Samuel Katz, Richard A Flavell, Karen S Anderson, Marcus Bosenberg, Goran Micevic.

Chronic stimulation of CD8⁺ T cells within the tumor microenvironment (TME) induces a hypofunctional state characterized by diminished cytotoxicity and functionally impaired anti-tumor function, known as exhaustion. Exhaustion is associated with epigenetic changes that remain relatively stable despite interventions like immune checkpoint inhibition (ICI). Although epigenetic changes are potentially reversible, reports of therapeutic strategies to effectively restore function in exhausted CD8⁺ T cells remain limited. Here, we report DNA methyltransferase 1 (DNMT1) inhibition (DNMT1i) in counteracting CD8 + T cell dysfunction during the anti-tumor response. We show that DNMT1i synergizes with ICI to rescue the tumor cell killing activity of chronically stimulated CD8⁺ T cells in a melanoma model. DNMT1i mitigates transcriptional features of exhaustion while inducing a divergent effector program. DNMT1i attenuates the global increase in chromatin accessibility associated with exhaustion and enables epigenetic remodeling of the exhausted chromatin landscape upon restimulation. Finally, DNMT1i enhances the effector function of melanoma patient-derived tumor infiltrating lymphocytes after prolonged ex vivo expansion. These studies establish DNMT1 targeting as a promising strategy to counteract CD8⁺ T cell exhaustion and potentiate ICI efficacy.

DOI: https://doi.org/10.64898/2026.07.03.736412
Immunity. 2026 Jul 13. pii: S1074-7613(26)00263-3. [Epub ahead of print]

MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion.

Tanmana Mitra, Jahan Rahman, Madeline Hwee, Yan-Ting Chen, Ruben Jose Jesus Faustino Ramos, Hui Liu, Travis Hartman, Justin Cross, Miguel de Jesus, Morgan Huse, Valerie Longo, Pat Zanzonico, Santosha A Vardhana.

  Loss of mitochondrial function promotes CD8+ T cell dysfunction during persistent antigen encounter. Here, we examined the pathways whereby chronic antigen stimulation leads to metabolic dysfunction. Chronic T cell receptor (TCR) engagement increased ATP demand, leading to mitochondrial NADH accumulation, accumulation of reactive oxygen species, and subsequent mitochondrial dysfunction. Among TCR-dependent proximal signaling components, inhibiting the kinase MEK uniquely reduced nutrient uptake and mitochondrial NADH accumulation while restoring proliferation. Accordingly, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II C-terminal domain phosphorylation, reducing transcription rates at loci encoding effector- and terminal-exhaustion-associated genes while maintaining transcription of genes associated with T cell memory. Thus, MEK-dependent metabolic demand is a driver of T cell exhaustion, providing insight into how MEK inhibition enhances immunotherapy efficacy.

Keywords:  NADH; RNA polymerase II; T cell exhaustion; bioenergetics; metabolism; mitochondria; nascent transcription; redox balance; terminal exhaustion; translation

DOI:  https://doi.org/10.1016/j.immuni.2026.06.012
Front Immunol. 2026 ;17 1744549

Ablating Satb1 reprograms the differentiation trajectory of exhausted CD8+ T subsets to enhance antitumor immunity.

Linwei Wu, Haolin Jiang, Jianling Gao, Xiaolan Ji, Yu Chen, Zhenghao Ma, Xinying Li, Jin Wang, Yachen Zang, Ji Zhang, Xin Zhao, Xuefeng Wang.

   Introduction: Under chronic infections or in tumors, persistent antigen exposure drives CD8+ T cell exhaustion, a heterogeneous state encompassing a differentiation continuum from stem-like progenitor (Tpex) cells through transitory effector-like (Tex-int) cells to terminally exhausted (Tex-term) subsets. Among these T cell subsets, Tex-int cells serve as the primary population responsible for direct tumor cell killing. However, the intrinsic regulatory mechanisms that govern the Tpex-to-Tex-int transition remain incompletely defined.
Methods: In this study, we explore the role of special AT-rich sequence-binding protein 1 (SATB1) in the differentiation of Tex-int cells from their precursors. We observed downregulation of SATB1 during Tpex-to-Tex-int differentiation in tumors. Notably, the genetic ablation of Satb1 in T cells markedly expanded the population of tumor-infiltrating CD8+ T cells (CD8+ TILs).
Results: Ablating Satb1 not only promoted the differentiation of Tex-int cells from Tpex cells within the tumor microenvironment but also remodeled T cell differentiation in tumor-draining lymph nodes (TdLNs) by expanding the Tpex pool from tumor-specific memory CD8+ T cells (TTSM) and driving the Tpex1 to Tpex2 transition, thereby augmenting Tex-int production in tumors. Although early-stage Tex-int cells in Satb1-deficient mice displayed transient functional impairment relative to controls, this difference was no longer evident in late-stage tumors, where sustained Tex-int accumulation correlated with significantly suppressed tumor growth and prolonged survival.
Discussion: Our results identify SATB1 as a pivotal regulator of exhausted CD8+ T cell subset differentiation and suggest its targeting as a promising strategy to expand the Tex-int population for enhanced cancer immunotherapy.

Keywords:  Satb1; Tex-int cells; Tpex cells; effector-like Tex- int cells; stem-like Tpex cells; tumor immunity; tumor-infiltrating CD8+ T cells

DOI:  https://doi.org/10.3389/fimmu.2026.1744549
Front Immunol. 2026 ;17 1755657

NOSIP overexpression promotes long-term persistence of CD8+ T cells during chronic infection.

Shihui Li, Toshikatsu Tamai, Yui Shinzawa, Sotaro Fujisawa, Yamato Tanabe, Makoto Utsunomiya, Hidetoshi Nakagawa, Junko Kurachi, Miki Koura, Eishiro Mizukoshi, Makoto Kurachi.

  Chronic antigen exposure drives CD8+ T cell exhaustion; however, strategies to maintain a long-lived, functional CD8+ T cell population under chronic stimulation remain unclear. In this study, we demonstrate that overexpression of nitric oxide synthase-interacting protein (NOSIP) enhances the persistence of antigen-specific CD8+ T cells under chronic antigen stimulation. Notably, NOSIP overexpression preserved a less differentiated CX3CR1neg subset and inhibited its progression toward an apoptosis-prone CX3CR1hi state, which was associated with reducing cell death and promoting long-term persistence. In a tumor model, NOSIP-overexpressing CD8+ T cells exhibited improved tumor control, indicating that NOSIP-mediated persistence confers superior antitumor capacity. Furthermore, NOSIP overexpression increased the responsiveness of CD8+ T cells to programmed death-ligand 1 blockade, suggesting that NOSIP may represent a promising therapeutic target.

Keywords:  CD8+ T cells; CX3CR1 subset differentiation; NOSIP; PD-L1 blockade responsiveness; chronic antigen stimulation

DOI:  https://doi.org/10.3389/fimmu.2026.1755657
Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2536238123

IL-7-glucose-Aiolos axis orchestrates pathogenic CD8+ T cell function in spondyloarthritis.

Mitsuhiro Akiyama, Waleed Alshehri, Mirei Koroyasu, Tomohiro Kaburaki, Keiko Yoshimoto, Koichi Saito, Kanako Shimanuki, Yuko Kaneko.

  CD8+ T cells are essential mediators of host defense, whereas their aberrant activation contributes to inflammatory diseases such as spondyloarthritis. The molecular mechanisms governing human CD8+ T cell effector programming remain incompletely understood. Here, we identify a metabolically distinct subset of human CD8+ T cells defined by high expression of CXCR3, IL-7R, and GLUT1 and low expression of the transcription factor Aiolos. IL-7-JAK-STAT signaling was associated with increased GLUT1 expression and glucose uptake, accompanied by reduced Aiolos expression in CD8+ T cells. Consistent with this, Aiolos functioned as a regulatory constraint on effector cytokine production under glucose-limited conditions, and its reduction was associated with enhanced cytokine production in metabolically active CD8+ T cells. Circulating CD8+ T cells from patients with spondyloarthritis exhibited elevated GLUT1 expression compared with rheumatoid arthritis and healthy controls, which correlated with disease activity. In addition, CXCR3+ IL-7R+ pSTAT5+ GLUT1+ Aioloslow CD8+ T cells were enriched in inflamed joints, where CXCL10 may contribute to their recruitment. Increased FDG uptake in inflamed sacroiliac joints further supports enhanced metabolic activity at sites of inflammation. JAK inhibitor therapy was associated with reduced GLUT1 expression and increased Aiolos expression in CD8+ T cells, accompanied by decreased effector cytokine production and clinical improvement in patients with spondyloarthritis. Together, these findings support a model in which cytokine signaling, metabolic state, and transcriptional regulation are functionally linked in human CD8+ T cells, and suggest that Aiolos may act as a regulatory node integrating these inputs in inflammatory diseases.

Keywords:  Aiolos; CD8+ T cells; Interleukin-7; Janus kinase; glucose transporter

DOI:  https://doi.org/10.1073/pnas.2536238123
J Cell Biochem. 2026 Jul;127(7): e70111

Glucose Metabolism in Immune Regulation: From Mechanisms to Therapeutic Opportunities.

Takhellambam Malemnganba, Anurag Kumar Pandey, Sramona Kar, Vijay Kumar Prajapati.

  Immune cell activation and differentiation are tightly coupled to metabolic reprogramming, with glucose availability and intracellular glycolytic flux serving as central determinants of immune cell fate and function. While increased glucose uptake and aerobic glycolysis support rapid proliferation and effector programs, persistent glucose abundance or dysregulated glycolytic signaling can contribute to immune dysfunction, chronic inflammation, and impaired host defense. Conversely, controlled limitation of glucose availability-through altered systemic supply, tissue microenvironmental competition, or targeted modulation of glycolysis-can rebalance immune metabolism toward oxidative phosphorylation, fatty acid oxidation, and mitochondrial fitness. This review examines how glucose availability and glycolytic flux operate as metabolic checkpoints that integrate with nutrient-sensing pathways, including mTORC1, AMPK, and HIF-1α, to shape immune activation, effector differentiation, and memory formation. We discuss evidence across disease contexts, including hyperglycemia-associated immune dysfunction, viral infection, autoimmunity, and cancer, and summarize emerging strategies to therapeutically modulate glucose metabolism using dietary interventions and pharmacologic tools. By distinguishing dietary carbohydrate intake from systemic glucose availability and cell-intrinsic glycolytic control, this review provides a coherent framework for understanding when glucose modulation can enhance immunity and when it risks immune suppression or metabolic exhaustion.

Keywords:  antiviral immunity; cancer immunotherapy; glucose availability; glycolytic flux; hyperglycemia; immunometabolism

DOI:  https://doi.org/10.1002/jcb.70111
J Immunother Cancer. 2026 Jul 15. pii: e013536. [Epub ahead of print]14(7):

Sleeping Beauty mutagenesis identifies BACH2 and other regulators of CD8+ T-cell exhaustion, persistence in vivo, and CAR-T cell function under tumor-associated chronic antigen stimulation.

Chang-Jung Lee, Alex T Larsson, Tyler A Jubenville, Wendy A Hudson, Zach J Seeman, Carli Stewart, Alexander K Tsai, Adam Burrack, Brooke L Kimball, Elizabeth L Siegler, Vianca V Vianzon, Erin E Nolan, Yu-Ling Yang, Christopher M Stehn, Daryl M Gohl, Margaret Donovan, Nuri A Temiz, Flavia E Popescu, Søren Warming, Somasekar Seshagiri, Yun You, Jesse D Riordan, Adam Dupuy, Branden Moriarity, Laura Rogers, Ingunn Stromnes, Saad Kenderian, David Largaespada.

   BACKGROUND: Genes that enhance T-cell function represent promising targets for improving engineered T-cell therapies for cancer. While extensive CRISPR knockout screens have identified key genes enhancing T-cell persistence, employing Sleeping Beauty (SB) insertional mutagenesis, which induces both gain-of-function (GOF) and loss-of-function (LOF) mutations via the generation of fusion transcripts with endogenous genes, may uncover additional critical factors that previous approaches have overlooked.
METHODS: We developed transgenic mice carrying Doxycycline (Dox)-inducible SB mutagenesis system (DiSBey) in primary T cells. Using DiSBey, we conducted screens for genetic alterations enhancing T-cell persistence under chronic antigen exposure. Specifically, CD8+ T cells from Dox-fed DiSBey mice were subjected to repeated anti-CD3 stimulation over 18 days to mimic chronic antigenic stimulation. We then identified SB transposon genomic insertion sites and corresponding fusion transcripts from the persistent DiSBey CD8+ T cells using enhanced-specificity tagmentation sequencing and RNA sequencing, respectively.
RESULTS: Under chronic stimulation, SB-mutagenized CD8+ T cells exhibited improved persistence and reduced terminal exhaustion phenotype. Across six independent screens, we identified 38 genes that were recurrently targeted by the SB transposon T2/Onc2 and differentially expressed under chronic anti-CD3 stimulation. T2/Onc2 insertions into Bach2 and Elmo1 were recurrently identified at the genomic level and were associated with altered nascent transcript expression. Bach2, known as a key regulator of T-cell memory formation and resistance to chronic viral infection-induced exhaustion but less characterized in engineered T cells for cancer therapy, was found to counteract exhaustion in vitro and enhance in vivo tumor persistence in the B16-Ova tumor model. Further, we showed that ectopic Bach2 expression levels influence engineered T-cell differentiation lineage, as low Bach2 overexpression retained more functional progenitor exhausted T cells and exhibited improved therapeutic efficacy. Finally, in human CART19-28ζ cells, BACH2 overexpression enhanced cytotoxicity and tumor control following chronic cancer stimulation.
CONCLUSIONS: Controllable SB mutagenesis using DiSBey mice provides a novel platform for functional screening of genes that improve T-cell phenotypes important for their use as therapies. Our findings highlight a dose-dependent role of BACH2 in enhancing the function of engineered T cells under conditions of chronic antigenic stimulation.

Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Gene expression profiling - GEP; Next generation sequencing - NGS; T cell

DOI:  https://doi.org/10.1136/jitc-2025-013536
bioRxiv. 2026 Jul 09. pii: 2026.07.05.736571. [Epub ahead of print]

CXCR6 marks polyfunctional effector CD4 T cells required for anti- Chlamydia immunity in the female reproductive tract.

Miguel A B Mercado, Yejin Kim, Qiang Li, Lin-Xi Li.

CD4 T cells are essential for protective immunity against Chlamydia in the female reproductive tract (FRT), yet the characteristics of protective mucosal effector CD4 T cells remain poorly defined. We previously identified the transcription factor BHLHE40 as a key regulator of polyfunctional effector CD4 T cell differentiation during Chlamydia infection. Here, we identify the chemokine receptor CXCR6 as a marker of these protective T cells. Following intravaginal Chlamydia muridarum infection, Bhlhe40 -deficient mice exhibited reduced frequencies of CXCR6⁺ CD4 T cells that correlated with impaired bacterial control. CXCR6 expression on T cells was associated with loss of stem-like features and acquisition of an effector phenotype. Compared with CXCR6⁻ cells, CXCR6⁺ CD4 T cells displayed enhanced proliferation and polyfunctionality by co-producing cytokines IFN-γ, IL-17A, and GM-CSF. Although CXCR6 was dispensable for CD4 T cell homing to the FRT, it promoted localization to the infected epithelium and the emerging memory lymphoid clusters. Importantly, depletion of CXCR6⁺ CD4 T cells reduced polyfunctional effectors and impaired bacterial clearance. Collectively, these findings identify CXCR6 as a marker of protective polyfunctional CD4 T cells and implicate CXCR6-dependent tissue positioning as a key component of effective mucosal immunity, highlighting CXCR6 as a potential biomarker for Chlamydia vaccine development.

DOI: https://doi.org/10.64898/2026.07.05.736571
Int J Mol Sci. 2026 Jul 02. pii: 5958. [Epub ahead of print]27(13):

Single-Cell Pan-Cancer Atlas Reveals GPR171 as a Candidate Marker of CD8+ T-Cell Dysfunction.

Xinyu Pan, Ao Zhang, Yuanyan Xiong.

  CD8+ T-cell exhaustion is a key mechanism of tumor immune evasion and a major limitation of current cancer immunotherapy. However, the molecular factors sustaining dysfunctional CD8+ T-cell states across cancers are not fully understood. Here, we identify GPR171 as a common feature of exhausted CD8+ T cells across multiple solid tumors based on integrated pan-cancer single-cell transcriptomic analyses. GPR171 is enriched in exhausted CD8+ T cells and is closely associated with immunosuppressive and exhaustion-related gene programs. It also shows a strong association with key immune regulatory genes such as CTLA4 and NR4A2. Functional analyses suggest that reduced GPR171 activity is associated with decreased expression of exhaustion-related genes and a shift toward cytotoxic and immune-activating programs. In parallel, a CREM-centered regulatory network emerges in exhausted CD8+ T cells and may act in concert with GPR171-associated programs to reinforce dysfunctional states. Overall, our results identify GPR171 as a candidate marker of CD8+ T-cell dysfunction across cancers and provide a systematic pan-cancer single-cell characterization of its association with immunosuppressive T-cell states, supporting its potential as a therapeutic target for restoring antitumor immunity.

Keywords:  CD8+ T-cell exhaustion; GPR171; immune checkpoint; immunosuppression; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms27135958
bioRxiv. 2026 Jul 09. pii: 2026.07.03.731744. [Epub ahead of print]

Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate.

Tom Sidwell, Ellen V Rothenberg.

Virtual memory T cells are increasingly recognized as a functionally distinct lineage within the CD8 T cell pool, but when and how commitment to the lineage is enforced remain poorly understood. Here we demonstrate that T VM lineage choice is exceptionally sensitive to dosage and repression competence of the key T cell transcription factor Bcl11b. Three different genetic models of slightly reduced Bcl11b each biased CD8 cell development to T VM generation without deregulating effector differentiation. Timed conditional knockouts and adoptive transfers narrowed the developmental window and showed that Bcl11b levels determine diversion to virtual memory fate uniquely during intrathymic positive selection. Whereas total Bcl11b loss disrupts TCR signalling, a <2-fold dose reduction of Bcl11b enhanced selective responses to TCR stimulation. Chromatin accessibility profiling and single cell RNA-seq indicated that Bcl11b dose reduction redirects cells to the T VM fate, from the late cycling fraction of mature CD8SP thymocytes, by a mechanism independent of previously described cytokine-driven pathways.

DOI: https://doi.org/10.64898/2026.07.03.731744
bioRxiv. 2026 Jul 07. pii: 2026.07.02.736105. [Epub ahead of print]

PSGL-1 blockade delays relapse to BRAF/MEK inhibition in cutaneous melanoma.

O S El Naggar, B N Ha, M L Rakoto, L Cort, A Amirfallah, E A Haglund, P Urquiza, Haf Hetrick, L M Bradley, E J Hartsough, J L Hope, G Romano.

Advanced BRAF-mutant cutaneous melanoma can be treated with targeted therapy when immune checkpoint inhibitors (ICIs) fail or are not a feasible option. Nevertheless, most patients do not achieve a durable response, highlighting the critical need for therapeutic partners that enhance the long-term efficacy of targeted therapy. Transcriptomic analysis of a BRAF-mutant melanoma model of acquired resistance identified P-selectin glycoprotein ligand-1 (PSGL-1) as a top-upregulated immune mediator upon resistance acquisition. PSGL-1 is a key regulator of CD8 + T cell exhaustion and differentiation, and its inhibition has been shown to enhance T cell function across multiple disease models. Based on these observations, we hypothesized that combined targeting of BRAF/MEK and PSGL-1 would improve anti-tumor responses. Here, we demonstrate that dual inhibition of BRAF/MEK and PSGL-1 elicits durable tumor control in a preclinical model of PD-1-refractory cutaneous melanoma. Single-cell RNA sequencing of the tumor microenvironment reveals robust reprogramming of intratumoral CD8 + T cells toward a less terminally differentiated, memory-like phenotype following combined BRAF/MEK and PSGL-1 targeting. Consistent with these findings, CD8 + T cells in the tumor-draining lymph nodes of PSGL-1 -/- mice exhibit enhanced functionality and a less differentiated state of exhaustion when compared with wild-type mice. To extend these observations to a translationally relevant setting, we further show that antibody-mediated blockade of PSGL-1, in combination with BRAF/MEK inhibition, yields superior anti-tumor activity compared with either monotherapy. Collectively, these findings identify PSGL-1 as a promising therapeutic target to enhance the durability of targeted therapy and provide a strong rationale for future clinical evaluation.

DOI: https://doi.org/10.64898/2026.07.02.736105
Immunity. 2026 Jul 14. pii: S1074-7613(26)00268-2. [Epub ahead of print]59(7): 1782-1784

CD4+ T cells persist with their Eomes.

Abishek Vaidya, Alice O Kamphorst.

Similar to CD8+ T cells, stem-like CD4+ T cells sustain responses to tumors, chronic infections, and inflammation. In this issue of Immunity, Wen et al. and Agesta et al. reveal EOMES as a critical regulator of stem-like CD4+ T cell maintenance and differentiation.

DOI: https://doi.org/10.1016/j.immuni.2026.06.017
Sci Rep. 2026 Jul 15.

Expression of the switch receptor PD1/IL15Rβ in MSLN-CAR-T cells overcomes PD1/PDL1 signaling in solid tumors.

Zahra Shahosseini, Tahereh Soltantoyeh, Hamid Reza Mirzaei, Kayhan Azadmanesh, Arash Arashkia, Jamshid Hadjati, Mohammad M Farajollahi.

  The immunosuppressive tumor microenvironment (TME) limits the efficacy of chimeric antigen receptor (CAR) T cells in solid tumors by inducing T cell exhaustion through inhibitory receptors, such as PD1 and TIM3. T memory stem cells (TSCMs) offer superior persistence, and IL15 promotes T cell memory. We engineered MSLN-CAR-T cells with a PD1/IL15Rβ switch receptor to convert PD1/PDL1 inhibitory signals into IL15-mediated STAT5 activation, enhancing T cell function. We developed MSLN-PD1/IL15Rβ-CAR-T cells, incorporating a PD1/IL15Rβ switch receptor, and evaluated their antitumor activity against pancreatic (AsPC-1, PANC-1) and cervical (HeLa) cancer cell lines. Proliferation, cytokine production (IL-2, IFN-γ), exhaustion markers (PD1, TIM3), and memory T cell phenotypes (CD45RO+/CCR7+) were assessed using flow cytometry, ELISA, and western blotting, with or without anti-PD1 antibody (Nivolumab) stimulation. MSLN-PD1/IL15Rβ-CAR-T cells exhibited enhanced STAT5 phosphorylation, significantly increased proliferation, and elevated IL-2 and IFN-γ secretion compared to MSLN-CAR-T cells when co-cultured with mesothelin- and PDL1-positive tumor cells or treated with Nivolumab. These cells exhibited reduced PD1 and TIM3 expression, along with a higher proportion of CD45RO+/CCR7 + memory T cells, suggesting decreased exhaustion and enhanced persistence. The PD1/IL15Rβ switch receptor overcomes PDL1-mediated immunosuppression in MSLN-CAR-T cells by activating STAT5 signaling, improving proliferation, cytokine production, and memory T cell formation while reducing exhaustion. This approach holds promise for enhancing CAR-T cell therapy in mesothelin-expressing solid tumors.

Keywords:  MSLN-CAR-T cells; Memory T cells; PD1/IL15Rβ switch receptor; PD1/PDL1 signaling; STAT5 activation; T cell exhaustion

DOI:  https://doi.org/10.1038/s41598-026-62555-7
Mol Ther Oncol. 2026 Sep 17. 34(3): 201277

Augmenting CAR T cell functionality and metabolism through CD39 downtuning.

Dennis Christoph Harrer, Jeremy Baldwin, Markus Barden, Hong Pan, Bence Gergely, Árpád Szöőr, György Vereb, Wolfgang Herr, Hinrich Abken.

  The CD39/CD73 axis is a potent intrinsic repressor of T cell functionality. CAR T cell activation triggers the increase of CD39; its downregulation reduced extracellular ATP degradation and enhanced the functional capacities in CD39low CAR T cells compared with conventional CAR T cells with respect to an increase in granzyme/perforin and degranulation upon repetitive CAR stimulation. CD39low CAR T cells, moreover, displayed superior mitochondrial function and enhanced glycolytic activities. Consequently, CD39low CAR T cells outperformed conventional CAR T cells in controlling CEA+ gastric carcinoma in xeno-transplanted NSG mice. The CD39 effect is unique, since downtuning CD38, also involved in the regulation of exhaustion, did not provide benefits under stimulatory "stress conditions". Activation-induced upregulation of CD39/CD73 contributes to a negative feedback loop for CAR T cells; downregulated CD39 levels augmented T cell anti-tumor activities by reducing AMP and adenosine-mediated repression. In the broader context, CD39 downregulation is unlikely to be sufficient as a standalone intervention in all settings but may be particularly valuable as part of combination strategies with complementary approaches targeting additional metabolic or immune checkpoint pathways to further enhance CAR T cell persistence and anti-tumor activity.

Keywords:  CAR T cell; CD39; adenosine; adoptive T cell therapy; exhaustion; metabolism

DOI:  https://doi.org/10.1016/j.omton.2026.201277
Trends Cell Biol. 2026 Jul 17. pii: S0962-8924(26)00132-7. [Epub ahead of print]

Immune cell lncRNAs reprogram the tumor microenvironment.

Chaitali Bhadiadra, Chunru Lin, Liuqing Yang.

  Long noncoding RNAs (lncRNAs) regulate the tumor microenvironment (TME), yet their cell-intrinsic roles within immune populations of the TME remain underappreciated. In this review, we shift focus from the cancer cell to the immune compartment, systematically reviewing how immune cell-intrinsic lncRNAs govern CD8+ T cell exhaustion, CD4+ T cell polarization, NK cell cytotoxicity, dendritic cell antigen presentation, and macrophage inflammatory programming. We highlight lncRNAs that function as molecular switches-tipping immune cells between antitumor effector and immunosuppressive states-and examine how exosomal lncRNAs extend these regulatory circuits across cellular boundaries within the TME. Finally, we evaluate opportunities for lncRNA-based biomarkers and therapies designed to target the immune landscape, outlining a framework for integrating immune-intrinsic lncRNA biology into precision immuno-oncology.

Keywords:  T cell exhaustion; immune cell-intrinsic lncRNAs; long noncoding RNAs; macrophage polarization; precision immuno-oncology; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tcb.2026.06.011
Cancer Immunol Res. 2026 Jul 16.

CD4+ T cells play distinct roles during the priming versus effector phases of immune checkpoint therapy-dependent tumor elimination by CD8+ T cells.

Samuel Ameh, Derek J Theisen, Mahima Thapa, Jackson S Turner, Abhinav Rangarajan, Christopher A Nelson, Aaron J Schmitz, Yuang Song, Ruan F Vieira Medrano, Cora D Arthur, J Michael White, Kathleen C F Sheehan, Daved H Fremont, Ali H Ellebedy, Hussein Sultan, Robert D Schreiber.

It is well established that CD4⁺ T cells play a critical role in facilitating immune checkpoint therapy (ICT). Although CD4+ T-cell function in lymph nodes during CD8⁺ T-cell priming has been well investigated, their requirement at the effector phase in the tumor is only now beginning to be appreciated. Herein, we used our major histocompatibility complex class II-negative (MHC-II-) sarcoma models to confirm that CD4⁺ T cells are essential not only during T-cell priming, but also to maintain T-cell effector function within the tumor. Depleting CD4⁺ T cells at the effector phase, after CD8+ T-cell priming had occurred, abolished ICT-induced tumor rejection despite the detection of tumor-specific CD8⁺ T cells and their intratumoral accumulation. CD4⁺ T cells were required for functional reinvigoration of CD8⁺ tumor-infiltrating lymphocytes (TIL) by ICT, leading to enhanced cytokine production, expression of cytotoxicity, and reduced exhaustion-without affecting CD8+ T-cell proliferation. Mechanistically, CD4⁺ T-cell function at the effector phase did not require CD40/CD40L signaling, which is necessary for efficient priming, but rather depended on IL-2 and IFNγ. Using a TCR-mimic monoclonal antibody (1G10) specific for the dominant neoantigen:I-Aᵇ complex on antigen-presenting cells formed during T3 sarcoma challenge, we further showed that ongoing MHC-II neoantigen presentation was necessary to sustain CD4⁺ T-cell help after priming. These findings reveal temporally distinct requirements for CD4⁺ T-cell help and establish a need for continuous CD4⁺/CD8⁺ T-cell cooperation as a prerequisite for anti-PD-1/anti-CTLA-4 ICT efficacy against MHC-II- tumors.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-1652
bioRxiv. 2026 Jul 09. pii: 2026.07.03.736145. [Epub ahead of print]

Confined T cell migration controls programmed cell death 1 expression.

Yunus Alapan, Jaehoon Kim, Kiyoon Min, Alexander Shih, Samuel N Lucas, Taehee Yoon, Paul A Archer, Heather K Lin, Ruby Freeman, Megen C Wittling, Megan M Wyatt, Chrystal M Paulos, Sarwish Rafiq, Susan N Thomas.

T cell immune checkpoint expression and dysfunction are attributed solely to molecular cues. We discover using microphysiological systems and in vivo models that transmigration through confined pores induces acute loss of programmed cell death 1 within minutes of surface immune checkpoint markers on CD8+ T cells through ubiquitin-mediated proteasomal degradation, corresponding with enhanced fitness and function. Such imprints and its underlying mechanism of programmed cell death 1 loss are conserved across species and applicable to human TIL and CAR T cells, and are correlative with disease outcomes in human melanoma. Our findings establish the diverse tissues landscapes that T cells traverse during immunosurveillance, and specifically transmigration, as a form of mechanical immune regulation, and reveal a mechano-modulatory strategy to improve the quality and persistence of engineered or patient-derived T cells for adoptive immunotherapy.

DOI: https://doi.org/10.64898/2026.07.03.736145
Cancers (Basel). 2026 Jun 25. pii: 2059. [Epub ahead of print]18(13):

The Relationship Between Neutrophil Extracellular Traps and CD8+ T Lymphocytes in Cancer: A Comprehensive Review of Current Data.

Kellyn E McKee, Hongji Zhang, Allan Tsung, Samantha M Ruff.

  Neutrophil extracellular traps (NETs) are web-like structures composed of decondensed DNA, histones, and proteins released by activated neutrophils. Originally identified as an innate defense mechanism against pathogens, NETs have since been implicated in cancer progression and immune evasion. Within the tumor microenvironment (TME), NETs suppress anti-tumor immunity through multiple mechanisms, including the physical exclusion of CD8+ cytotoxic T lymphocytes from the tumor interior and upregulation of exhaustion markers via checkpoint ligands. This review synthesizes current preclinical and clinical evidence on the interplay between NETs and CD8+ T cells across multiple malignancies, including non-small cell lung cancer, pancreatic ductal adenocarcinoma, cholangiocarcinoma, colorectal cancer, bladder cancer, hepatocellular carcinoma, skin cancer, and penile cancer. Cancer-specific mechanisms of NET-mediated immune suppression are discussed, including IL-8, IL-17, CXCL6, and TGF-β-driven NETosis pathways. Clinical data consistently demonstrate that elevated NET levels correlate with reduced CD8+ T cell infiltration, T cell dysfunction, and worse patient outcomes. Emerging therapeutic strategies targeting this axis are reviewed, including DNase I-mediated NET degradation, Peptidyl arginine deiminase 4 (PAD4) inhibition, CXCR2 blockade, and combination approaches with immune checkpoint inhibitors. These interventions have shown promise in restoring CD8+ T cell cytotoxicity and overcoming immunotherapy resistance in preclinical models. Collectively, the evidence supports the NET-CD8+ T cell axis as a promising prognostic and therapeutic target warranting further clinical investigation.

Keywords:  CD8+ T cells; NETosis; cancer; immune evasion; immunotherapy; neutrophil extracellular traps; neutrophils

DOI:  https://doi.org/10.3390/cancers18132059
Nat Commun. 2026 Jul 14.

Disrupting fumarylacetoacetate hydrolase by stratified nanoplatforms orchestrates metabolic-immune reprogramming and prevents post-ablation HCC relapse.

Zhiwen Hong, Xiaolong Liu, Rouhan A, Zengzhen Chen, Qianjiang Wu, Jixian Fu, Xue Guan, Can Wang, Xinghua Wang, Shan Jiang, Bolong Li, Zhaobo Wang, Lei Zhang, Xianwei Meng, Yali Cui, Tengchuang Ma.

Hepatocellular carcinoma (HCC) recurrence following microwave ablation poses a pressing clinical challenge, driven by metabolically adapted residual cells that establish an immunosuppressive tumour microenvironment. Our study identifies the post-ablation upregulation of fumarylacetoacetate hydrolase (FAH) as a crucial "metabolic checkpoint" promoting relapse. Elevated FAH expression results in increased fumarate levels within residual HCC cells, supporting tumour cell survival by enhancing energy metabolism while concurrently impairing CD8+ T cell function. Mechanistically, fumarate binds to and stabilises heat shock protein 70 (HSP70), establishing a thermal ablation induced FAH-fumarate-HSP70 axis that drives immunosuppression. To counteract this pivotal axis, we engineered a gallium-based functionalized nanoplatform. This system incorporates a lactate oxidase shell that responds to the lactate-rich tumour microenvironment, enabling the site-specific co-release of Ga3+, FAH-silencing plasmids and the glycolysis inhibitor 2-deoxy-D-glucose. Our nanoplatforms disrupt the FAH-fumarate-HSP70 axis to eradicate residual HCC, activate CD8+ T cells, and restore immunity, targeting recurrence dysregulation while integrating metabolic blockade with immunomodulation to prevent post-ablation relapse with clinical translation potential.

DOI: https://doi.org/10.1038/s41467-026-75422-w
bioRxiv. 2026 Jul 07. pii: 2026.07.02.735504. [Epub ahead of print]

NK-like and networked CD8 + T cell immunity mediates exceptional HIV control.

Aljawharah Alrubayyi, Anna K Traunbauer, Charles R Crain, Shaown Bhattacharyya, David R Collins, Hsinyen Huang, Clarety Kaseke, Umar Arshad, Xiaodong Lian, Aarthi Vijayakumar, Matthew A Getz, Mathias Lichterfeld, Xu G Yu, Bruce D Walker, Georg M Lauer, Gaurav D Gaiha.

Durable treatment-free remission remains a defining goal for people living with HIV (PLWH). Studies of spontaneous elite controllers have revealed that functional CD8⁺ T cells targeting structurally networked viral epitopes can mediate durable viral suppression 1,2 . However, rare reservoir-defined exceptional controllers within the spectrum of elite control 3-5 , characterized by the absence of intact provirus or proviruses confined to transcriptionally repressed genomic regions 6 , provide a unique opportunity to define mechanisms of cure-like immunity. Here, we integrate functional epitope mapping, single-cell transcriptomics, and infected cell elimination assays to identify networked HIV epitope targeting and a natural killer (NK)-like killer-cell immunoglobulin-like receptor (KIR)⁺ CD8⁺ T cell subset as key features of exceptional control. This NK-like subset was selectively enriched within HIV-specific, but not CMV-specific, CD8⁺ T cells from controllers, and was transcriptionally similar to highly cytotoxic subsets within the broader KIR + CD8 + T cell compartment. Flow cytometry revealed increased frequencies of KIR⁺ CD8⁺ T cells in exceptional controllers relative to antiretroviral therapy (ART)-suppressed individuals, and unexpectedly, enrichment of dual KIR + NKG2A + CD8⁺ T cells. Functional depletion of KIR⁺ CD8⁺ T cells significantly impaired the elimination of autologous HIV-infected CD4⁺ T cells, despite preserved recognition by proliferative networked HIV-specific CD8⁺ T cells. These findings thereby identify an NK-like KIR⁺ CD8⁺ T cell state as a previously unrecognized component of exceptional HIV immunity that complements networked epitope targeting, providing a novel framework for immunotherapeutic HIV cure strategies.

DOI: https://doi.org/10.64898/2026.07.02.735504
bioRxiv. 2026 Jul 11. pii: 2026.07.07.737119. [Epub ahead of print]

Intrinsic T-cell programming and immune spatial organization govern sex-biased tuberculosis immunity.

Manish Gupta, Stefanie Krug, Sarita Neupane, Moagi Shaku, Sabal Chaulagain, Shichun Lun, Joseph P Hoffmann, Eileen Scully, Sabra L Klein, William R Bishai.

Biological sex can profoundly influence the susceptibility to infectious diseases, yet the mechanisms behind the sex-dependent protective immunity against tuberculosis (TB) remain poorly understood. Here we show that sexually divergent immunity during chronic Mycobacterium tuberculosis (Mtb) infection is governed by both intrinsic T cell programming and pulmonary immune spatial organization. Using the Four Core Genotype (FCG) mouse model, adoptive cell transfer, pathway-specific blockade and B cell depletion, we demonstrate that CD4⁺ T cells from gonadal females (XXF), but not XX males (XXM), confer enhanced protection to susceptible XY male recipients, independently of sex chromosome complement. Female-derived CD4⁺ T cells reduce Mtb burdens while promoting pulmonary Bcl6⁺ CD4⁺ T cell responses and limiting neutrophilic inflammation. Mechanistically, blockade of CXCR3 or CD40L abrogates female-associated protection, with CD40L signaling additionally required to maintain organized pulmonary B cell structures. Although depletion of conventional B-2 B cells did not impair bacterial control, it disrupted tertiary lymphoid organization and revealed striking sex-specific functions of pulmonary B cells. Loss of B cell follicles (BCFs) primarily remodeled adaptive T cell responses in females, whereas in males it drove inflammatory myeloid activation, exaggerated neutrophil recruitment and widespread neutrophil extracellular trap (NET) formation. Together, these findings identify two complementary layers of sex-dependent immune regulation during TB: intrinsic programming of protective female CD4⁺ T cells, and B cell-dependent spatial organization that coordinates adaptive immunity in females while restraining pathological inflammation in males. These findings establish immune tissue organization as a key determinant of the sexually dimorphic host defense during chronic TB.

DOI: https://doi.org/10.64898/2026.07.07.737119
Mol Ther Oncol. 2026 Sep 17. 34(3): 201280

Reversible control of CAR T cells through PROTAC compound targeting bromodomain mutant.

Yeongrin Kim, Da Yeon Lee, Ji U Choi, Moonjung Jeun, Heung Kyoung Lee, Sang Un Choi, Chi Hoon Park.

  Proteolysis-targeting chimera (PROTAC) is an innovative strategy for selectively degrading target proteins. In this study, we demonstrate that a PROTAC compound, AGB1, specifically degrades a bromodomain L387V mutant (BD2m)-tagged chimeric antigen receptor (CAR-BD2m). Unlike ARV771, which degrades wild-type bromodomains, AGB1 does not impair normal T cell function, as it spares endogenous bromodomain-containing proteins such as BRD4. Notably, AGB1 degrades CAR-BD2m with approximately 10-fold higher efficiency than ARV771 targets the wild-type BD2-tagged CAR (CAR-BD2w). In vitro, AGB1 reversibly modulates the activity of CAR-BD2m T cells through targeted CAR degradation. In preclinical models, CAR-BD2m T cells exhibit potent antitumor activity comparable to that of conventional CAR T cells, and AGB1 effectively regulates the activity of CAR-BD2m T cells. Together, these results suggest that the BD2m system can serve as an efficient tagging platform for targeted CAR protein degradation, thereby enabling successful and reversible control of CAR T cell activity in patients.

Keywords:  CAR T cells; PROTAC; adoptive immunotherapy; cancer; reversible control

DOI:  https://doi.org/10.1016/j.omton.2026.201280
Mol Biol Rep. 2026 Jul 17. pii: 1192. [Epub ahead of print]53(1):

Differential NAD + availability may drive asymmetric SIRT7 activity in tumor and immune cells.

Francisco Alejandro Lagunas-Rangel.

  Metabolic competition within the tumor microenvironment shapes the availability of nutrients and metabolites that regulate both tumor progression and antitumor immunity. Among the molecules linking metabolism to gene regulation, the NAD + -dependent enzyme SIRT7 has emerged as an important regulator of ribosome biogenesis, genome stability, chromatin organization, and metabolic adaptation. Although SIRT7 is frequently associated with tumor progression, emerging evidence indicates that it also supports the metabolic fitness and effector functions of immune cells, suggesting that its biological consequences are highly cell type-dependent. However, the mechanisms underlying these apparently opposing functions remain poorly understood. A conceptual framework is presented in which differences in intracellular NAD + availability contribute to asymmetric SIRT7 activity in tumor and immune cells within the tumor microenvironment. Many tumor types preserve intracellular NAD + through metabolic rewiring, whereas infiltrating immune cells frequently experience sustained metabolic stress and progressive NAD + depletion owing to nutrient competition. Although direct evidence demonstrating that physiological fluctuations in intracellular NAD + regulate SIRT7 activity in vivo remains limited, biochemical studies indicate that SIRT7 displays a relatively high apparent Michaelis constant (Km) for NAD + compared with other mammalian sirtuins, providing a biochemical rationale for increased sensitivity to changes in intracellular NAD + availability. Current evidence from SIRT7 biology, cancer metabolism, and immunometabolism is integrated to evaluate this conceptual framework, identify key limitations in the available data, and highlight experimental questions that should be addressed to determine whether differential NAD + availability represents a fundamental mechanism underlying the context-dependent functions of SIRT7.

Keywords:  Immune dysfunction; PD-L1; Sirtuin; T cells; Tumor microenvironment

DOI:  https://doi.org/10.1007/s11033-026-12400-x
bioRxiv. 2026 Jul 09. pii: 2026.07.08.737054. [Epub ahead of print]

Distinct macrophage and T cell programs shape pancreatic inflammation during metabolic stress and aging.

Somesh Sai, Ibrahim Omar, Matthias Barone, Kerstin Mühle, Maria Schneider, Fenfen Liu, Sharanya Sriram, Juliette Claire Johnson, Tizia Thoma, Thomas Conrad, Tatiana Borodina, Birgit Sawitzki, Maike Sander, Han Zhu.

Type 2 diabetes is linked to systemic inflammation driven by metabolic stress and aging. Although pancreatic inflammation associated with these factors is well documented, the dynamics of immune cell populations and their molecular changes remain poorly understood. We characterized immune cell alterations in the pancreas and pancreatic islets during Western diet (WD) feeding and aging using imaging mass cytometry (IMC) and single-cell RNA sequencing (scRNA-seq). Spatial and transcriptional analyses were performed to define immune cell subtype composition, activation states, and inferred cell-cell communication programs under metabolic and age-related stress conditions. Our analyses identified expansion of an F4/80 low macrophage subtype and activated effector-like CD8 + T cells throughout the pancreas during WD feeding and aging. Within pancreatic islets, single-cell RNA sequencing identified a type I interferon-responsive macrophage population with low F4/80 expression that expanded during overnutrition. Notably, the type I interferon responses elicited by these stressors diverged: aging was associated with a more canonical type I interferon response, whereas overnutrition induced a broader response that included STAT3-associated transcriptional programs. We further provide evidence for enhanced cytokine-mediated communication between macrophages and a CD8 + cytotoxic T-cell population under overnutrition and aging. These findings show that metabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms, involving expansion of F4/80 low macrophages, activation of divergent type I interferon programs, and enhanced macrophage-CD8 + T-cell communication. Together, these findings suggest that distinct therapeutic approaches may be required to preserve islet function in type 2 diabetes driven by metabolic stress versus aging.
Article Highlights: Metabolic stress and aging remodel pancreatic inflammation through overlapping but distinct immune mechanisms.Spatial and single-cell analyses identified conserved remodeling of pancreatic macrophage populations accompanied by activation of cytotoxic T-cell responses during metabolic stress and aging.In pancreatic islets, macrophages exhibited distinct type I interferon-associated transcriptional programs, with aging showing a more canonical interferon response and metabolic stress eliciting a broader inflammatory program that included STAT3-associated transcriptional signatures.These findings provide a framework for understanding how metabolic stress and aging differentially shape pancreatic inflammation.

DOI: https://doi.org/10.64898/2026.07.08.737054
Br J Cancer. 2026 Jul 11.

TP53 mutation-biased CD8+ T cell exhaustion drives lethal outcome and therapy resistance in urothelial carcinoma.

Xiaohe Su, Kaifeng Jin, Han Zeng, Zhaopei Liu, Lingkai Zhang, Yawei Ding, Jiaxing Sun, Yuzhen Wu, Hailong Liu, Yuan Chang, Le Xu, Weijuan Zhang, Zewei Wang, Yu Zhu, Jiejie Xu.

BACKGROUND: Emerging evidence has underscored non-cell-autonomous roles of mutant p53 in reshaping the composition and functional state of tumour immune microenvironment (TIME). However, the impact of p53 status on the clinical relevance and functional differentiation of CD8+ T cells remains poorly understood in urothelial carcinoma (UC).
METHODS: Our study included 297 UC patients from two in-house cohorts and 871 UC patients from four public datasets to evaluate the impact of p53 status on the clinical implications of CD8+ T cells. Single-cell RNA sequencing, flow cytometry, immunohistochemistry, and bioinformatics analyses were performed to elucidate the role of p53 status in regulating CD8+ T cell polarisation and reshaping the TIME.
RESULTS: High CD8+ T cell infiltration correlated with favourable prognosis and improved survival following chemotherapy and PD-(L)1 blockade exclusively in p53-WT UC, while its association with prognosis and therapeutic benefit was abrogated in p53-mutant UC. Moreover, p53-mutant UC exhibited predominant infiltration of TIM3+ exhausted CD8+ T cells, accompanied by increased Treg and M2 macrophage infiltration.
CONCLUSIONS: The clinical significance and functional polarisation of CD8+ T cells in UC varied in a context-dependent manner according to p53 status. These findings provide novel insights to refine patient stratification and optimise personalised therapeutic strategies.

DOI: https://doi.org/10.1038/s41416-026-03548-1
Nat Cancer. 2026 Jul 15.

A targetable micropeptide reprograms macrophages to suppress T cell anti-tumor immunity.

DOI: https://doi.org/10.1038/s43018-026-01196-1
Mol Biol Rep. 2026 Jul 15. pii: 1163. [Epub ahead of print]53(1):

From barrier to trigger: leveraging tumor hypoxia for precise control of CAR-T cell activity.

Parisa Pedram Rad, Ali Reyhani, Mohammadreza Dashti.

  CAR-T cell therapy has revolutionized the treatment of hematologic malignancies, yet its translation to solid tumors remains a formidable challenge. A central determinant of this limitation is the hypoxic tumor microenvironment, which imposes profound immunosuppressive pressure on infiltrating CAR-T cells, impairing their persistence, effector function, and metabolic fitness. Rather than viewing hypoxia purely as an obstacle, emerging engineering paradigms are reframing it as a tumor-selective switch one that can be harnessed to spatially confine CAR-T cell activation, enhance metabolic fitness, and reduce off-tumor toxicity. This review critically examines how hypoxia subverts CAR-T cell immunity, and how next-generation hypoxia-responsive constructs, metabolic reprogramming strategies, and armored cytokine-secreting designs are beginning to turn this hostile microenvironment into a therapeutic advantage. We further discuss unresolved clinical challenges and the translational outlook for hypoxia-adapted CAR-T cells in solid tumor immunotherapy.

Keywords:  CAR-T cell therapy; HIF-1α; Hypoxia; Immunotherapy; Metabolic reprogramming; Solid tumors; Tumor microenvironment

DOI:  https://doi.org/10.1007/s11033-026-12321-9
Front Immunol. 2026 ;17 1859721

Perspective: Hormones and immune development: bidirectional regulation between thyroid hormones and the immune system.

Weiling Zhang, Sitao Huang, Yingying Kang, Qingquan Zhao, Sixian Cheng, Zhengrong Zheng.

  The immune system operates within a dynamic physiological environment shaped by systemic regulatory signals, among which endocrine factors are increasingly recognized as important modulators of immune function. Although thyroid hormones are well known for their roles in metabolism and development, their contribution to adaptive immunity, particularly in regulating T cell responses, remains incompletely understood. Emerging evidence suggests that thyroid-immune interactions are context-dependent across physiological and pathological conditions. In this Perspective, we propose that thyroid hormone signaling acts as a systemic regulator of T cell responses, integrating endocrine, immune, and metabolic cues to fine-tune immune activity. Mechanistically, this regulation involves thyroid hormone receptor-mediated pathways, interactions with cytokine networks, and immunometabolic programs that influence T cell differentiation and function. Clinically, thyroid dysfunction is associated with altered immune tolerance, autoimmune disease progression, and broader immune-related outcomes. Despite increasing interest in endocrine-immune crosstalk, current models remain fragmented. Future studies integrating longitudinal and multi-omics approaches are needed to better define thyroid-immune regulation and identify potential therapeutic targets.

Keywords:  T cell regulation; autoimmunity; endocrine–immune interactions; immune homeostasis; immunometabolism; reproductive immunology; thyroid hormones

DOI:  https://doi.org/10.3389/fimmu.2026.1859721
Immunohorizons. 2026 Jul 10. pii: vlag039. [Epub ahead of print]10(7):

Medium chain fatty acid sensing receptor GPR84 limits antitumor immunity mediated by CD4 T cells in mice.

Anamaria Morales-Alvarez, Timothy A Gilbertson, Hung Nguyen.

  CD4+ T cells play an important role in antitumor immunity due to their capacity to acquire highly functional effector states and cytotoxic-like programs in the tumor microenvironment. However, the mechanisms underlining this process remain largely undefined. Herein, we identify the medium chain fatty acid-sensing receptor GPR84 as a metabolic checkpoint that restricts the antitumor immunity mediated by CD4+ T cells. GPR84 upregulation was detected in tumor-infiltrating CD4+ T cells, and in the absence of GPR84, CD4+ T cells exhibited enhanced tumor control, associated with increase in their proliferation and survival, and with a reprogramming toward a more functionally competent state characterized by increased polyfunctional cytokine production and reduced expression of inhibitory receptors, without accumulation of regulatory T cells. In the tumor antigen-specific mouse model, GPR84 deficiency drastically improved the therapeutic efficacy of adoptively transferred CD4+ T cells. Mechanistically, without GPR84, CD4+ T cells, by upregulating mTORC1 signaling activity, metabolically enhance both glycolysis and mitochondrial activities, thereby gearing toward tumor-killing cytotoxic phenotypes. Importantly, pharmacologic inhibition of GPR84 drastically improves the effectiveness of both PD-1 blockade therapy and adoptive cell transfer. Together, these findings validate GPR84 as a key regulator of CD4+ T-cell metabolic fitness and establish the extracellular lipid sensing pathway as a targetable axis for improving the efficacy and responsiveness of cancer immunotherapies.

Keywords:  GPR84; cancer immunotherapy; cytotoxic CD4+ T cells; immunometabolism; medium chain fatty acids

DOI:  https://doi.org/10.1093/immhor/vlag039
Science. 2026 Jul 16. 393(6808): eadx8675

A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.

Alex C Sternisha, Haocheng Li, Kumar Gajendra, Yi Xiao, Xin Zhao, Jeffrey I Traylor, Lei Guo, Ji Hyung Jun, Morgan Fleishman, Tracey Shipman, Vinesh T Puliyappadamba, Pranita Kaphle, Qing Ouyang, Michael Schmidt, Diana D Shi, Milan R Savani, Alexander C-Y Tsai, Joyce H Lee, Ruth Gordillo, Javier Garcia-Bermudez, Yoon Jung Kim, Shih-Chia Tso, Chad A Brautigam, Lauren G Zacharias, Thomas P Mathews, Lin Xu, John G Doench, Vidyasagar Koduri, Kalil G Abdullah, Michalis Agathocleous, Laura A Banaszynski, Ralph J DeBerardinis, Eric M Morrow, Samuel K McBrayer.

The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.

DOI: https://doi.org/10.1126/science.adx8675
Int J Mol Sci. 2026 Jul 05. pii: 6037. [Epub ahead of print]27(13):

What Do We Know About Immune System Aging from Human and Animal Studies?

Marta Cąkała-Jakimowicz, Anna Domaszewska-Szostek, Monika Puzianowska-Kuźnicka.

  Aging is accompanied by complex structural and functional immune system changes driven by genomic instability, epigenetic alterations, mitochondrial dysfunction, telomere attrition, loss of proteostasis, deregulated nutrient sensing, and the accumulation of senescent cells exhibiting a senescence-associated secretory phenotype, which altogether lead to severe consequences including altered antimicrobial defense, the overproduction of autoantibodies, and chronic, low-grade inflammation (inflammaging). In this article, we summarize age-related alterations in the function of primary and secondary lymphoid organs, including the bone marrow, thymus, spleen, and lymph nodes. The involution of these organs leads to impaired hematopoiesis, reduced production of naïve lymphocytes, and immune microenvironment disruption. We also describe aging-related impairment of the activity of neutrophils, macrophages, dendritic cells and natural killer cells, as well as dysregulation of T and B lymphocyte responses. Specifically, these alterations include a decline in naïve cell populations, an accumulation of memory and exhausted cells, and a reduction in the diversity of antigen receptors. Consequently, older individuals exhibit increased susceptibility to infections, cancer, and autoimmune diseases, along with diminished vaccine efficacy. Understanding the mechanisms underlying immune aging could lay the foundation for developing therapeutic strategies and lifestyle interventions to mitigate the adverse effects of this unfavorable process.

Keywords:  aging; immunosenescence; inflammaging

DOI:  https://doi.org/10.3390/ijms27136037
Nat Metab. 2026 Jul 14.

Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.

Jiayin Tang, Gerard Pernes, Brenda Nakagaki, Nhien Tran, Laura Bokor, Fran Prenen, Mingyang Yi, Avery E Robertson, Rachel Cronin, Mohamad Sarmini, Jacob Pierscianowski, Victoria Roberts, Birgitta A Ryback, Carl D Novina, Karine Auclair, Haopeng Xiao, Evanna L Mills.

Thermogenic brown and beige adipose tissues are important in maintaining metabolic health because of their distinct ability to catabolize stored fat and circulating glucose in futile cycles1,2. Macrophages, present in brown adipose tissue, have been reported to both positively and negatively regulate thermogenic adipocyte function through mechanisms that are incompletely understood3-14. Here we show that the macrophage-derived metabolite, itaconate, acts as a paracrine signal to repress adipose tissue thermogenesis in mice. Mechanistically, itaconate inhibits thermogenesis by antagonizing uptake of the pro-thermogenic metabolite, succinate, into brown adipose tissue. These findings reveal an unexpected mechanism for local control of thermogenesis in vivo that relies on paracrine itaconate signalling and demonstrate that the important signalling roles of itaconate extend beyond immunological processes to the regulation of energy balance.

DOI: https://doi.org/10.1038/s42255-026-01572-2
Int Immunopharmacol. 2026 Jul 13. pii: S1567-5769(26)00973-2. [Epub ahead of print]186 117127

Immuno-metabolic reprogramming in pulmonary fibrosis: Emerging therapeutic targets beyond inflammation.

Hemraj Singh, Anushka Purwar, Rajeev Taliyan.

  Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive extracellular matrix deposition, tissue remodeling, and irreversible loss of lung function. Although inflammation contributes to disease progression, increasing evidence indicates that immunometabolic reprogramming is a central driver of fibrotic persistence. Alterations in glycolysis, mitochondrial function, lipid metabolism, and redox homeostasis actively regulate immune responses, fibroblast activation, and epithelial cell dysfunction, thereby sustaining a profibrotic microenvironment. This review synthesizes current advances in understanding how metabolic pathways regulate immune and structural cell behavior during pulmonary fibrosis. Particular emphasis is placed on metabolic checkpoints, including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and nicotinamide adenine dinucleotide (NAD+)-dependent signaling, which integrate metabolic and inflammatory responses. We further discuss how mitochondrial dysfunction, hypoxia-inducible factor-1α (HIF-1α), reactive oxygen species (ROS), cellular senescence, and metabolic memory contribute to disease persistence. Emerging evidence supports metabolic crosstalk between immune cells and fibroblasts as a key mechanism driving fibrotic remodeling. Finally, we evaluate therapeutic strategies targeting immunometabolic pathways and discuss current translational challenges, including cellular heterogeneity, pathway redundancy, and limited clinical validation. Collectively, this review highlights immunometabolic regulation as a promising therapeutic framework and identifies opportunities for precision-based interventions in pulmonary fibrosis.

Keywords:  AMPK; Fibroblast activation; Glycolysis; Immunometabolism; Metabolic memory; Metabolic reprogramming; Mitochondrial dysfunction; Pulmonary fibrosis; Therapeutic targeting; mTOR signaling

DOI:  https://doi.org/10.1016/j.intimp.2026.117127
Front Cell Dev Biol. 2026 ;14 1826809

Ammonia metabolic reprogramming in the tumor microenvironment: emergence of an immunosuppressive niche.

Zihao Ye, Hao Wu, Zhanhao Li, Ruizhe Ye, Yingliang Rao, Bin Liu, Baoshan Gao.

  Metabolic reprogramming within the tumor microenvironment plays a pivotal role in tumor proliferation, progression, and immune evasion. Cancer cells exhibit altered lipid, glucose, and amino acid metabolism to adapt to hostile conditions such as hypoxia and nutrient deprivation. Particularly, ammonia metabolism has emerged as a critical aspect of tumor metabolic reprogramming. Oncogene mutations, such as those in c-MYC, KRAS, and p53, regulate key enzymes involved in amino acid metabolism, which in turn affects tumor cell survival and proliferation. Elevated ammonia levels in the TME (Tumor Microenvironment) not only provide essential nitrogen for cell growth but also impair immune cell function, including T cells and natural killer cells, contributing to immune evasion. High ammonia concentrations suppress T cell activation and promote exhaustion, while interfering with natural killer cell cytotoxicity by hindering perforin maturation. Moreover, ammonia accumulation fosters an immunosuppressive microenvironment, influencing cytokine secretion and facilitating tumor metastasis. Targeting ammonia metabolism, in combination with immune checkpoint inhibitors, presents a promising therapeutic strategy to enhance immune responses and inhibit tumor progression. This review consolidates recent findings on the role of ammonia metabolism in the TME, highlighting its potential as a therapeutic target to improve cancer treatment outcomes.

Keywords:  SLC (solute carrier family); TME (tumor microenvironment); ammonia metabolism; cancer; metabolic reprogram

DOI:  https://doi.org/10.3389/fcell.2026.1826809
Front Immunol. 2026 ;17 1863647

NAFLD-associated immune remodeling in colorectal cancer liver metastasis: mechanisms and implications for immunotherapy.

Hui Wang, Guoqing Gu.

  Non-alcoholic fatty liver disease (NAFLD) affects over 30% of the global adult population and has been increasingly recognized as an adverse prognostic factor for colorectal cancer (CRC) liver metastasis (CRLM). However, the underlying immune mechanisms remain incompletely understood. This review provides a comprehensive synthesis of how NAFLD-induced lipotoxicity reshapes the hepatic immune microenvironment to create a "fertile soil" for CRC metastatic colonization. We delineate a hierarchical immunosuppressive network involving: (1) lipotoxic apoptosis of CD4+ T cells, depleting the helper T cell pool; (2) expansion and functional reinforcement of regulatory T cells (Tregs) through multiple mechanisms (IL-10/TGF-β/IL-35, CD25-mediated IL-2 competition, CTLA-4 engagement, and granzyme B/perforin production); (3) M2 polarization of tumor-associated macrophages; and (4) recruitment of myeloid-derived suppressor cells (MDSCs) via the CXCL5/CXCR2 axis, which suppress CD8+ T cell function. These processes collectively promote CD8+ T cell exhaustion (marked by PD-1, LAG-3, TIM-3 upregulation) and spatial mismatch with metastatic foci. Importantly, we discuss the emerging evidence linking NAFLD-driven immune dysregulation to reduced responsiveness to immune checkpoint inhibitors, while acknowledging the current limitations in direct clinical validation. By integrating mechanistic insights with therapeutic perspectives, this review offers new targets for risk stratification and combination immunotherapy in the growing NAFLD population. Non-alcoholic fatty liver disease.

Keywords:  CD8+ T cell exhaustion; colorectal cancer liver metastasis; immunosuppressive network; immunotherapy; myeloid-derived suppressor cells; non-alcoholic fatty liver disease; regulatory T cells

DOI:  https://doi.org/10.3389/fimmu.2026.1863647
Front Immunol. 2026 ;17 1881243

The mitochondrial logic of inflammaging: how energy imbalance drives fibroblast SASP and tissue-specific aging.

Yu Huan, Qiqi Wang, Rongkaixuan Fang, Yue Sun, Meiya Suo, Chenghong Cao, Shuya Zhang, Lan A, Wenzhou Xu.

  The conversion of metabolic disequilibrium into chronic inflammatory signaling represents a central and actively investigated question in ageing biology. Among stromal cells, fibroblasts are key effectors of tissue remodeling and inflammation, acquiring a senescence-associated secretory phenotype (SASP) that sustains age-related pathology. Here, we delineate a mechanistic framework in which disruption of energy homeostasis drives mitochondrial dysfunction, innate immune activation, and SASP secretion. Mitochondria act as metabolic sentinels that sense energetic stress through altered AMP/ATP and NAD+/NADH ratios, leading to the generation of mitochondrial danger signals-reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA). These signals converge on canonical immune pathways, including the cGAS-STING axis, NLRP3 inflammasome, and NF-κB signaling, thereby converting metabolic distress into persistent pro-inflammatory output. Using periodontal ligament fibroblasts as a disease-relevant model, we highlight how microbial biofilm exposure induces mitochondrial metabolic reprogramming that amplifies fibroblast SASP, promotes osteoclastogenesis, extracellular-matrix degradation, and alveolar bone resorption. At the transcriptional level, regulatory networks involving NF-κB, C/EBPβ, STATs, and the mTOR-AMPK hub integrate mitochondrial signals to sustain inflammatory senescence. We propose that restoring mitochondrial metabolic homeostasis serves as a highly promising strategy to break the self-perpetuating cycle in which energy imbalance triggers SASP activation, which in turn contributes to chronic inflammation. Researchers must first characterize the tissue-specific mitochondrial signatures of SASP. Subsequently, developing precise, lesion-targeted metabolic interventions will open new avenues for mitigating inflammaging and rejuvenating stromal function across ageing tissues.

Keywords:  cellular senescence; fibroblasts; inflammaging; innate immune signaling; metabolic reprogramming; mitochondrial dysfunction; senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.3389/fimmu.2026.1881243
Nat Commun. 2026 Jul 15.

The SIRT5-SUCLG2 desuccinylation axis delays ovarian aging via a mitochondrial-epigenetic regulatory mechanism.

Dejun Xu, Shuaifei Song, Qingmiao Shi, Zhiling Zhao, Wenhao Zhao, Lei Wang, Guangxin E, Yanguo Han, Yongju Zhao, Zhongquan Zhao.

Mitochondrial dysfunction and epigenetic alterations play critical roles in aging-related diseases, yet the molecular mechanisms linking mito-nuclear crosstalk to ovarian aging remain poorly understood. Here, single-cell transcriptome analysis of aging ovaries revealed senescence-associated hallmark alterations, including abnormally elevated mitochondrial metabolism, disrupted histone modification patterns, and enrichment of the senescence-associated secretory phenotype (SASP). We demonstrated that impaired SIRT5-mediated desuccinylation constitutes a key driver of ovarian aging. Mechanistically, we identified succinyl-coenzyme A (CoA) synthetase GDP-forming subunit β (SUCLG2) in the tricarboxylic acid (TCA) cycle as the main target of SIRT5-mediated desuccinylation. SUCLG2 desuccinylation at lysine residues K93 and K101 enhanced its protein stability and activity, thereby improving mitochondrial function upon cellular senescence. However, SUCLG2 hypersuccinylation specifically increased H4K8ac through acetyl-CoA accumulation in nucleus, leading to the overexpression of metabolism-related genes to compensate for the energy demand deficiency caused by decreased mitochondrial function during cellular senescence. In vivo functional studies demonstrated that acetyl-CoA oversupply accelerated ovarian aging, whereas ovarian gene therapy employing a SUCLG2 desuccinylation mutant ameliorated this condition. This study illuminates the molecular mechanisms underlying ovarian aging and identifies the SIRT5-SUCLG2 axis as a promising therapeutic target for age-related ovarian dysfunction.

DOI: https://doi.org/10.1038/s41467-026-75502-x