bims-imseme 2025-05-25 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–05–25
thirty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Meta-epigenetic shifts in T cell aging and aging-related dysfunction.
Aging Compromises Terminal Differentiation Program of Cytotoxic Effector Lineage and Promotes Exhaustion in CD8+ T Cells Responding to Coronavirus Infection.
Physical Activity Modifies the Metabolic Profile of CD4+ and CD8+ T-Cell Subtypes at Rest and Upon Activation in Older Adults.
Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.
S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer.
Deciphering the role of histone modifications in memory and exhausted CD8 T cells.
Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment.
Editorial: Enhancing T cell function: innovations in cancer immunotherapy.
Mechanisms of CD8+ T cell exhaustion and its clinical significance in prognosis of anti-tumor therapies: A review.
Magnetic Bead-Based Isolation of CD8+ T Cells from the Mouse Spleen.
The Bacterial Outer Membrane Vesicle-Cloaked Immunostimulatory Nanoplatform Reinvigorates T Cell Function and Reprograms Tumor Immunity.
Author Correction: Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
From powerhouse to modulator: regulating immune system responses through intracellular mitochondrial transfer.
Anti-PD-1 antibody enhances homeostatic proliferation-induced antitumor immunity during lymphopenia recovery.
Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers.
T-Cell Senescence: Unlocking the Tumor Immune "Dark Box" - A Multidimensional Analysis from Mechanism to Tumor Immunotherapeutic Intervention.
An engineered viral protein activates STAT5 to prevent T cell suppression.
How Do Mitochondria Manage Competing Biochemical Metabolic Processes Under Stress?
Succinate reduces biological activity and mitochondrial function of human adipose-derived stem cells.
Gut-vitamin D interplay: key to mitigating immunosenescence and promoting healthy ageing.
The m6A demethylase FTO controls Th1 differentiation and immunity against infections.
Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration.
Restricting SLC7A5-mediated Leucine uptake in T cells prevents acute GVHD and maintains GVT response.
The Arf pathway is required for resolving ER stress during T cell activation.
Age-Related Oxidative Stress and Mitochondrial Dysfunction in Lymph Node Stromal Cells Limit the Peripheral T Cell Homeostatic Maintenance and Function.
Unravelling cysteine-deficiency-associated rapid weight loss.
Single-cell transcriptomics reveals metabolic remodeling and functional specialization in the immune microenvironment of bone tumors.
Mitochondrial bioenergetic profiling in T cell subsets associates with functional health in older adults: A cross-sectional analysis from the INSPIRE-T cohort.
Beyond Canonical Immune Checkpoints: Overexpression of TNFRSF Members 4-1BB and OX-40 Marks T Cells Exhibiting Phenotypic Features of Exhaustion in Cervical Carcinoma.
CD8+ T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells.

J Biomed Sci. 2025 May 23. 32(1): 51

Meta-epigenetic shifts in T cell aging and aging-related dysfunction.

Lorène Rousseau, Karina L Hajdu, Ping-Chih Ho.

  Epigenetic regulation, including DNA methylation and histone modifications, play a pivotal role in shaping T cell functionality throughout life. With aging, these epigenetic changes profoundly affect gene expression, altering T cell plasticity, activation, and differentiation. These modifications contribute significantly to immunosenescence, increasing susceptibility to infections, cancer, and autoimmune diseases. In CD8⁺ T cells, chromatin closure at key regulatory regions suppresses activation and migration, while chromatin opening in pro-inflammatory gene loci amplifies inflammation. These changes drive terminal differentiation, characterized by increased expression of senescence-associated markers, impaired migration and loss of epigenetic plasticity. CD4⁺ T cells experience fewer but critical epigenetic alterations, including disrupted pathways, a skewed Th1/Th2 balance, and reduced Treg functionality. These epigenetic changes, compounded by metabolic dysfunctions, such as mitochondrial deficiency and oxidative stress, impair T-cell adaptability and resilience in the aging organism. Therefore, understanding the interplay between epigenetic and metabolic factors in T cell aging offers promising therapeutic opportunities to mitigate immunosenescence and enhance immune function in aging populations. This review explores the interplay between DNA methylation, histone alterations, and metabolic changes underlying T cell aging.

Keywords:  DNA methylation; Immune aging; Immunosenescence; T cell aging; T cell dysfunction; T cell metabolism

DOI:  https://doi.org/10.1186/s12929-025-01146-6
Aging Cell. 2025 May 21. e70109

Aging Compromises Terminal Differentiation Program of Cytotoxic Effector Lineage and Promotes Exhaustion in CD8+ T Cells Responding to Coronavirus Infection.

Ziang Zhu, Guohua Lou, Ying Luo, Kiddist Yihunie, Jonathan Hoar, Juan A Daniel, Bret M Evers, Chen Yao, Tuoqi Wu.

  T cell aging increases the risk of viral infection-related morbidity and mortality and reduces vaccine efficacy in the elderly. A major hallmark of T cell aging is the loss of quiescence and shift toward terminal differentiation during homeostasis. However, how aging impacts the differentiation program of virus-specific T cells during infection is unclear. Here, in a murine coronavirus (MHV) infection model with age-associated increased mortality, we demonstrate that aging impairs, instead of promoting, the terminal differentiation program of virus-specific CD8+ T cells. Upon infection, CD8+ and CD4+ T cells in old mice showed marked reduction in clonal expansion and upregulation of immune checkpoints associated with T cell exhaustion. Bulk and single-cell transcriptomics showed that aging upregulated the T cell exhaustion transcriptional program associated with TOX in virus-specific CD8+ T cells and shifted the myeloid compartment from immunostimulatory to immunosuppressive phenotype. In addition, aging downregulated the transcriptional program of terminally differentiated effector CD8+ T cells and diminished the CX3CR1+ cytotoxic effector lineage. Mechanistically, virus-specific CD8+ T cells from infected aged mice displayed defects in inducing transcription factors ZEB2 and KLF2, which were required for terminal differentiation of effector CD8+ T cells. Together, our study shows that aging impairs terminal differentiation and promotes exhaustion of virus-specific CD8+ T cells responding to coronavirus infection through dysregulating expression of lineage-defining transcription factors.

Keywords:  CD8+ T cells; aging; exhaustion; mouse hepatitis virus (MHV); terminally differentiated effector

DOI:  https://doi.org/10.1111/acel.70109
Aging Cell. 2025 May 21. e70104

Physical Activity Modifies the Metabolic Profile of CD4+ and CD8+ T-Cell Subtypes at Rest and Upon Activation in Older Adults.

Jon Hazeldine, Edward Withnall, Alba Llibre, Niharika A Duggal, Janet M Lord, Amanda V Sardeli.

  T-cell metabolism is a key regulator of immune function. Metabolic dysfunction in T cells from young mice results in an aged phenotype, accelerating immunosenescence. Physical activity (PA) maintains T-cell function and delays immunosenescence in older adults, but the underlying mechanisms are poorly understood. We investigated the effects of PA on the metabolic and functional profiles at a single-cell resolution of resting and stimulated T cells from young adults (N = 9, 23 ± 3 years) and physically active older adults clustered between higher PA (HPA, N = 9, 75.5 ± 4.7 years) or lower PA levels (LPA, N = 10, 76.4 ± 2.1 years). Compared to young donors, HPA older adults had higher mitochondrial dependence (MD) and lower glucose dependence (GD) in unstimulated naïve, central memory (CM) and effector memory (EM) CD4+ and EM CD8+ T cells, while LPA older adults had higher overall protein synthesis in naïve and EM CD4+ and CD8+. In response to PMA and Ionomycin stimulation, there was a similar increase in GD and a reduction in MD across groups for most T-cell subsets. Although LPA and HPA underwent a higher increase in protein synthesis upon activation compared to the young subjects, HPA did not exhibit the excessive increase in the percentage of IL-6+ T cells observed in the LPA group compared to young subjects. Taken together, our data provide evidence of a higher energy demand, impaired metabolic flexibility, and hyperinflammatory responses in aged T cells, and PA reduces metabolic demand in these cells, potentially through increased MD and improved metabolic flexibility.

Keywords:  T cell; aging; cellular immunology; cytokines; inflammation; mitochondria; senescence; training

DOI:  https://doi.org/10.1111/acel.70104
Nat Cancer. 2025 May 20.

Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.

Helen Carrasco Hope, Jana de Sostoa, Pierpaolo Ginefra, Massimo Andreatta, Yi-Hsuan Chiang, Catherine Ronet, Christine Pich-Bavastro, Jesús Corria Osorio, François Kuonen, Johan Auwerx, Patrizia D'Amelio, Ping-Chih Ho, Santiago J Carmona, George Coukos, Denis Migliorini, Nicola Vannini.

Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.

DOI: https://doi.org/10.1038/s43018-025-00982-7
Cancer Metab. 2025 May 19. 13(1): 23

S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer.

Xiaohua Yang, Tianzhang Kou, Hongmiao Wang, Ji Zhu, Zheng-Jiang Zhu, Yuping Cai.

  Metabolite nutrients within the tumor microenvironment shape both tumor progression and immune cell functionality. It remains elusive how the metabolic interaction between T cells and tumor cells results in different anti-cancer immunotherapeutic responses. Here, we use untargeted metabolomics to investigate the metabolic heterogeneity in patients with colorectal cancer (CRC). Our analysis reveals enhanced S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism in microsatellite stable (MSS) CRC, a subtype known for its resistance to immunotherapy. Functional studies reveal that SAM and SAH enhance the initial activation and effector functions of CD8+ T cells. Instead, cancer cells outcompete CD8+ T cells for SAM and SAH availability to impair T cell survival. In vivo, SAM supplementation promotes T cell proliferation and reduces exhaustion of the tumor-infiltrating CD8+ T cells, thus suppressing tumor growth in tumor-bearing mice. This study uncovers the metabolic crosstalk between T cells and tumor cells, which drives the development of tumors resistant to immunotherapy.

Keywords:  CD8+ T cell function; Metabolite nutrients; Metabolomics; Microsatellite stable colorectal cancer; S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism

DOI:  https://doi.org/10.1186/s40170-025-00394-2
Sci Rep. 2025 May 19. 15(1): 17359

Deciphering the role of histone modifications in memory and exhausted CD8 T cells.

Hua Huang, Amy E Baxter, Zhen Zhang, Charly R Good, Katherine A Alexander, Zeyu Chen, Paula A Agudelo Garcia, Parisa Samareh, Sierra M Collins, Karl M Glastad, Lu Wang, Gregory Donahue, Sasikanth Manne, Josephine R Giles, Junwei Shi, Shelley L Berger, E John Wherry.

Exhausted CD8 T cells (TEX) arising during chronic infections and cancer have reduced functional capacity and limited fate flexibility that prevents optimal disease control and response to immunotherapies. Compared to memory (TMEM) cells, TEX have a unique open chromatin landscape underlying a distinct gene expression program. How TEX transcriptional and epigenetic landscapes are regulated through histone post-translational modifications (hPTMs) remains unclear. Here, we profiled key activating (H3K27ac and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in naive CD8 T cells (TN), TMEM and TEX. We identified H3K27ac-associated super-enhancers that distinguish TN, TMEM and TEX, along with key transcription factor networks predicted to regulate these different transcriptional landscapes. Promoters of some key genes were poised in TN, but activated in TMEM or TEX whereas other genes poised in TN were repressed in TMEM or TEX, indicating that both repression and activation of poised genes may enforce these distinct cell states. Moreover, narrow peaks of repressive H3K9me3 were associated with increased gene expression in TEX, suggesting an atypical role for this modification. These data indicate that beyond chromatin accessibility, hPTMs differentially regulate specific gene expression programs of TEX compared to TMEM through both activating and repressive pathways.

DOI: https://doi.org/10.1038/s41598-025-99804-0
Nat Commun. 2025 May 19. 16(1): 4652

Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment.

Daniela Aviles-Huerta, Rossella Del Pizzo, Alexander Kowar, Ali Hyder Baig, Giuliana Palazzo, Ekaterina Stepanova, Cinthia Claudia Amaya Ramirez, Sara D'Agostino, Edoardo Ratto, Catarina Pechincha, Nora Siefert, Helena Engel, Shangce Du, Silvia Cadenas-De Miguel, Beiping Miao, Victor M Cruz-Vilchez, Karin Müller-Decker, Ilaria Elia, Chong Sun, Wilhelm Palm, Fabricio Loayza-Puch.

The tumor microenvironment (TME) influences cancer cell metabolism and survival. However, how immune and stromal cells respond to metabolic stress in vivo, and how nutrient limitations affect therapy, remains poorly understood. Here, we introduce Dual Ribosome Profiling (DualRP) to simultaneously monitor translation and ribosome stalling in multiple tumor cell populations. DualRP reveals that cancer-fibroblast interactions trigger an inflammatory program that reduces amino acid shortages during glucose starvation. In immunocompetent mice, we show that serine and glycine are essential for optimal T cell function and that their deficiency impairs T cell fitness. Importantly, immune checkpoint blockade therapy imposes amino acid restrictions specifically in T cells, demonstrating that therapies create distinct metabolic demands across TME cell types. By mapping codon-resolved ribosome stalling in a cell‑type‑specific manner, DualRP uncovers metabolic crosstalk that shapes translational programs. DualRP thus offers a powerful, innovative approach for dissecting tumor cell metabolic interplay and guiding combined metabolic-immunotherapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-59986-7
Front Immunol. 2025 ;16 1615030

Editorial: Enhancing T cell function: innovations in cancer immunotherapy.

Ji Zhang, Qihao Zhao, Qian Sun, Hong Jiang, Valentyn Oksenych, Xuefeng Wang.



Keywords:  CD8 + T cells; car-t; editorial: enhancing t cell function: innovations in cancer immunotherapy cancer immunotherapy; enhancing T cell function; stem-like CD8 + T cells

DOI:  https://doi.org/10.3389/fimmu.2025.1615030
Int Immunopharmacol. 2025 May 19. pii: S1567-5769(25)00833-1. [Epub ahead of print]159 114843

Mechanisms of CD8+ T cell exhaustion and its clinical significance in prognosis of anti-tumor therapies: A review.

Anrui Yang, Meng Zhou, Yixuan Gao, Ying Zhang.

  In recent years, immunotherapy has gradually become one of the main strategies for cancer treatment, with immune checkpoint inhibitors (ICIs) offering new possibilities for tumor therapy. However, some cancer patients exhibit low responses and resistance to ICIs treatment. T cell exhaustion, a process associated with tumor progression, refers to a subset of T cells that progressively lose effector functions and exhibit increased expression of inhibitory receptors. These exhausted T cells are considered key players in the therapeutic efficacy of immune checkpoint inhibitors. Therefore, understanding the impact of T cell exhaustion on tumor immunotherapy and the underlying mechanisms is critical for improving clinical treatment outcomes. Several elegant studies have provided insights into the prognostic value of exhausted T cells in cancers. In this review, we highlight the process of exhausted T cells and its predictive value in various cancers, as well as the relevant mechanisms behind it, providing new insights into the immunotherapy of cancer.

Keywords:  CD8(+) T cell exhaustion; Immune cells; Immune checkpoint inhibitors; Review; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2025.114843
Methods Mol Biol. 2025 ;2930 45-53

Magnetic Bead-Based Isolation of CD8+ T Cells from the Mouse Spleen.

Diego Quintana-Torres, Alejandra Valle-Cao, Alejandro López-Soto, Alicia R Folgueras.

  The immune system serves as a barrier limiting the initiation and progression of new tumors. Among its cellular components, CD8+ T cytotoxic cells are integral to the immune response against cancer. These cells can identify and combat tumor cells by releasing lytic granules, thereby driving the adaptive immune response. However, their function can be hindered by several factors such as immunosuppression in the tumor microenvironment, T cell exhaustion, and immunosenescence. Consequently, dissecting these mechanisms is essential to fully comprehend the immune response against cancer cells and can aid in tailoring future antitumor immunotherapies. In this chapter, we outline a straightforward method for isolating CD8+ T cells from the mouse spleen. These cells can then be further analyzed or utilized in in vitro functional studies, such as coculture with target tumor cells and assessing their cytotoxic activity and cytokine production profiling.

Keywords:  CD8+ T cells; Flow cytometry; Immune cell purification; Magnetic-activated cell sorting (MACS); Mouse spleen

DOI:  https://doi.org/10.1007/978-1-0716-4558-1_4
ACS Nano. 2025 May 20.

The Bacterial Outer Membrane Vesicle-Cloaked Immunostimulatory Nanoplatform Reinvigorates T Cell Function and Reprograms Tumor Immunity.

Yu-Han Lin, Chia-Wei Chen, Mei-Yi Chen, Li Xu, Xuejiao Tian, Siu-Hung Cheung, Yen-Ling Wu, Natnaree Siriwon, Si-Han Wu, Kurt Yun Mou.

  Bacterial outer membrane vesicles (OMVs) represent powerful immunoadjuvant nanocarriers with the capacity to reprogram the tumor microenvironment (TME) and activate immune responses. Here, we investigate a nanotherapeutic platform integrating immunostimulatory cytosine-phosphate-guanine oligodeoxynucleotides (CpG-ODNs, hereafter termed CpG) into mesoporous silica nanoparticles cloaked with OMVs (CpG@MSN-PEG/PEI@OMVs) for cancer immunotherapy. Systemic administration of these nanohybrids facilitates precise tumor targeting, induces antitumor cytokines such as IFNγ, and suppresses immunosuppressive cytokine TGF-β, reshaping the TME. Additionally, CpG@MSN-PEG/PEI@OMVs promote M1 macrophage polarization, dendritic cell maturation, and the generation of durable tumor-specific immune memory, resulting in pronounced tumor regression with minimal systemic toxicity. The platform demonstrates efficacy against metastatic and solid tumor models including 4T1 breast and MC38 colorectal cancers. Transcriptomic analyses reveal that CpG@MSN-PEG/PEI@OMVs enhance mitochondrial oxidative phosphorylation in T cells within tumor-draining lymph nodes, mitigating T cell exhaustion and restoring metabolic fitness. These results support the potential of CpG@MSN-PEG/PEI@OMVs as a modular nanoplatform to modulate innate and adaptive immunity in cancer immunotherapy.

Keywords:  T cell exhaustion phenotypes; bacterial outer membrane vesicles; mesoporous silica nanoparticles; mitochondrial activity; tumor microenvironment

DOI:  https://doi.org/10.1021/acsnano.5c02541
Nat Cell Biol. 2025 May 22.

Author Correction: Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.

Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P Praharaj, Stewart Morley, Bookyung Ko, Mona H Soflaee, Harrison J Tom, Harrison Brown, Hieu S Vu, Shih-Chia Tso, Chad A Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K Allen, Gerta Hoxhaj.

DOI: https://doi.org/10.1038/s41556-025-01695-w
Cell Commun Signal. 2025 May 20. 23(1): 232

From powerhouse to modulator: regulating immune system responses through intracellular mitochondrial transfer.

Mostafa Changaei, Zahra Azimzadeh Tabrizi, Mozhdeh Karimi, Seyed Adnan Kashfi, Tina Koochaki Chahardeh, Seyed Mahmoud Hashemi, Sara Soudi.

  Mitochondria are traditionally known as the cells' powerhouses; however, their roles go far beyond energy suppliers. They are involved in intracellular signaling and thus play a crucial role in shaping cells' destiny and functionality, including immune cells. Mitochondria can be actively exchanged between immune and non-immune cells via mechanisms such as nanotubes and extracellular vesicles. The mitochondria transfer from immune cells to different cells is associated with physiological and pathological processes, including inflammatory disorders, cardiovascular diseases, diabetes, and cancer. On the other hand, mitochondrial transfer from mesenchymal stem cells, bone marrow-derived stem cells, and adipocytes to immune cells significantly affects their functions. Mitochondrial transfer can prevent exhaustion/senescence in immune cells through intracellular signaling pathways and metabolic reprogramming. Thus, it is emerging as a promising therapeutic strategy for immune system diseases, especially those involving inflammation and autoimmune components. Transferring healthy mitochondria into damaged or dysfunctional cells can restore mitochondrial function, which is crucial for cellular energy production, immune regulation, and inflammation control. Also, mitochondrial transfer may enhance the potential of current therapeutic immune cell-based therapies such as CAR-T cell therapy.

Keywords:  Immune system; Immunometabolism; Immunotherapy; Mitochondria; Mitochondria Transfer; Organelle therapy

DOI:  https://doi.org/10.1186/s12964-025-02237-5
Front Immunol. 2025 ;16 1563894

Anti-PD-1 antibody enhances homeostatic proliferation-induced antitumor immunity during lymphopenia recovery.

Zike Yang, Ying Zhu, Qian Wang, Qing Lin, Yahui Liu.

   Introduction: Lymphopenia induced by radiotherapy or chemotherapy can promote homeostatic proliferation of residual or adoptive lymphocytes, potentially enhancing antitumor immunity. However, this immunity diminishes rapidly with tumor progression, and the underlying mechanisms remain unclear. This study investigates the role of PD-1 signaling in homeostatic proliferation-induced antitumor immunity in malignant melanoma.
Methods: We evaluated T-cell dynamics in lymphopenic mice, analyzing PD-1 expression, IFN-γ production by CD8+ T cells, and T-cell cytotoxicity during homeostatic proliferation. The PD-1/PD-L1 axis was blocked using anti-PD-1 antibodies to assess its impact on T-cell function, dendritic cell (DC) activation, and memory T-cell differentiation.
Results: Although T cells proliferated continuously in lymphopenic mice, IFN-γ+ CD8+ T cells declined over time. PD-1 expression on T cells increased progressively and correlated negatively with effector T-cell cytotoxicity. PD-1 blockade enhanced the recognition of tumor-associated antigens (TAAs) by homeostatically proliferating (HP) T cells, activated DCs, and increased IFN-γ+ CD8+ T-cell numbers. Additionally, it boosted T-cell cytotoxicity and promoted the conversion of tumor-specific effector T cells into central memory T cells.
Discussion: These findings indicate that the PD-1/PD-L1 axis plays a critical role in immune tolerance during homeostatic proliferation. Anti-PD-1 therapy may enhance antitumor immunity during lymphopenia recovery after chemotherapy or radiotherapy, offering a potential strategy to sustain T-cell-mediated tumor control.

Keywords:  PD-1/PD-L1; antitumor immunity; homeostatic proliferation; immunotherapy; lymphopenia; melanoma

DOI:  https://doi.org/10.3389/fimmu.2025.1563894
Nat Nanotechnol. 2025 May 21.

Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers.

Xueting Pan, Zhihang Wang, Mixiao Tan, Ziying Fu, Guangjun Nie, Hai Wang.

Cancer immunotherapy utilizing cytotoxic T lymphocytes has demonstrated significant promise in clinical applications, but cancer immunosuppressive mechanisms hamper further progress in T cell immunotherapy. Here we show a correlation between cancer cell mitochondrial content and their resistance to immunotherapy. Observing that cancer cells with higher mitochondrial content show increased resistance to CD8+ T cells, we developed mitochondrial nanoinducers designed to selectively target and degrade mitochondria within autophagosomes. The direct degradation of mitochondria not only enhances the recognition and activation of CD8+ T cells but also increases the susceptibility of cancer cells to CD8+ T cell-mediated cytotoxicity. We demonstrated the feasibility and efficacy of this strategy in multiple in vitro and in vivo tumour therapeutic models. This nanoinducer, designed to manipulate cellular mitochondrial degradation, holds promise as a versatile tool for enhancing adoptive T cell therapy, CAR-T cell therapy and tumour-vaccine-based immunotherapy.

DOI: https://doi.org/10.1038/s41565-025-01909-0
Semin Cancer Biol. 2025 May 15. pii: S1044-579X(25)00073-2. [Epub ahead of print]

T-Cell Senescence: Unlocking the Tumor Immune "Dark Box" - A Multidimensional Analysis from Mechanism to Tumor Immunotherapeutic Intervention.

Jia Cheng, Jian Zheng, Chen Ma, Yongzhang Li, Hua Hao.

  Immunosenescence is the dysfunction of the immune system that occurs with age, a process that is complex and characterized by several features, of which T-cell senescence is one of the key manifestations. In the tumor microenvironment, senescent T cells lead to the inability of tumor cells to be effectively eliminated, triggering immunosuppression, which in turn affects the efficacy of immunotherapy. This is a strong indication that T-cell senescence significantly weakens the immune function of the body, making individuals, especially elderly patients with cancer, more vulnerable to cancer attacks. Despite the many challenges, T-cell senescence is important as a potential therapeutic target. This review provides insights into the molecular mechanisms of T-cell senescence and its research advances in patients with cancer, especially in older adults, and systematically analyzes potential intervention strategies, including molecular mechanism-based interventions, the use of immune checkpoint inhibitors, and CAR-T cell therapy. It is hoped that this will establish a theoretical framework for T-cell senescence in the field of tumor immunology and provide a scientific and prospective reference basis for subsequent in-depth research and clinical practice on senescent T cells.

Keywords:  Cancer immunotherapy; Immune checkpoint inhibitor; Mechanism; T-cell senescence; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2025.05.010
Sci Immunol. 2025 May 23. 10(107): eadn9633

An engineered viral protein activates STAT5 to prevent T cell suppression.

Yating Zheng, Zehui Gu, Claire E Shudde, Taylor L Piper, Xinyu Wang, Grace A Aleck, Jiajia Zhou, Dana King, Monica K Chanda, Lilliana Trinch, Weiping Zou, Adam H Courtney.

T cell therapy efficacy can be compromised if cytokine-induced Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is dysregulated or insufficient to sustain functionality. Here, we demonstrate that LCK kinase activity can be recruited to noncanonical protein substrates to directly activate targeted STAT proteins in T cells. STAT activation was accomplished by engineering the herpesvirus saimiri tyrosine kinase interacting protein (TIP) to provide a platform for the enforced recruitment of LCK to STAT proteins. We determined that a minimal region of TIP that binds to LCK could be combined with STAT binding sites derived from endogenous cytokine receptors. These constructs activated targeted STAT proteins in a cytokine-independent manner. We identified a STAT5 activator that sustained CD8+ T cell survival and cytotoxic function ex vivo in the absence of interleukin-2. Tumor outgrowth was reduced in vivo because of enhanced T cell persistence and functionality. Single-cell transcriptomics revealed that the STAT5 activator prevented the expression of genes associated with an exhausted T cell fate. Our findings demonstrate that signaling pathways can be rewired in T cells to sustain their function in solid tumors.

DOI: https://doi.org/10.1126/sciimmunol.adn9633
Curr Protein Pept Sci. 2025 May 16.

How Do Mitochondria Manage Competing Biochemical Metabolic Processes Under Stress?

Drew Hindrer, Tyler Stark, Selman Aydogdu, Cade Ward, Mohamed Eldeeb.



Keywords:  Mitochondrial fission; mitochondrial fusion; mitochondrial quality control.; mitochondrial stress; molecular metabolism; redox reactions

DOI:  https://doi.org/10.2174/0113892037381885250506091434
Cell Cycle. 2025 May 20. 1-13

Succinate reduces biological activity and mitochondrial function of human adipose-derived stem cells.

Bo Wang, Xinxin Wang, Meijin Guo, Huiming Xu.

  Elevated succinate accumulation has been demonstrated to be associated with metabolic and inflammatory disorders. Our previous study revealed that adipose-derived stem cells (ADSC) from obese individuals exhibit high succinate, reduced biological activity, and mitochondrial dysfunction. However, the precise role of succinate in these processes remains unclear. Here, we investigated the effects of excess succinate on cellular biological activity, immunomodulatory capacity, and mitochondrial function of ADSC. We found that elevated succinate levels in ADSC decreased proliferation and differentiation potential, while promoting M1 macrophage polarization. Furthermore, succinate accumulation impaired mitochondrial biogenesis and metabolism, increasing in reactive oxygen species (ROS) production and inflammatory responses. Transcriptome sequencing analysis further confirmed that succinate upregulated inflammatory pathways, suppressed mitochondrial biogenesis and metabolism, and enhanced cellular apoptosis and senescence, accompanied by reduced DNA replication and repair. Overall, these findings imply that succinate accumulation in ADSC triggers inflammatory response and mitochondrial dysfunction, potentially contributing to a decline of cellular biological activity. Targeting succinate may offer therapeutic potential for metabolic disorders.

Keywords:  Succinate; adipose-derived stem cells; mitochondrial dysfunction; reduced biological activity

DOI:  https://doi.org/10.1080/15384101.2025.2508109
Immun Ageing. 2025 May 19. 22(1): 20

Gut-vitamin D interplay: key to mitigating immunosenescence and promoting healthy ageing.

Hammad Ullah.

   BACKGROUND: Immunosenescence is the loss and change of immunological organs, as well as innate and adaptive immune dysfunction with ageing, which can lead to increased sensitivity to infections, age-related diseases, and cancer. Emerging evidence highlights the role of gut-vitamin D axis in the regulation of immune ageing, influencing chronic inflammation and systemic health. This review aims to explore the interplay between the gut microbiota and vitamin D in mitigating immunosenescence and preventing against chronic inflammation and age-related diseases.
MAIN TEXT: Gut microbiota dysbiosis and vitamin D insufficiency accelerate immunosenescence and risk of chronic diseases. Literature data reveal that vitamin D modulates gut microbiota diversity and composition, enhances immune resilience, and reduce systemic inflammation. Conversely, gut microbiota influences vitamin D metabolism to promote the synthesis of active vitamin D metabolites with implications for immune health.
CONCLUSIONS: These findings underscore the potential of targeting gut-vitamin D axis to modulate immune responses, delay the immune ageing, and mitigate age-related diseases. Further research is needed to integrate vitamin D supplementation and microbiome modulation into strategies aimed at promoting healthy ageing.

Keywords:  Gut microbiota; Healthy ageing; Immune ageing; Immunosenescence; Vitamin D

DOI:  https://doi.org/10.1186/s12979-025-00514-y
Mol Immunol. 2025 May 15. pii: S0161-5890(25)00124-5. [Epub ahead of print]183 172-181

The m6A demethylase FTO controls Th1 differentiation and immunity against infections.

Zhihong Yao, Lina Sun, Yang Gao, Yanhong Su, Boxiao He, Yao Ge, Chen Yang, Xiaoxuan Jia, Anjun Jiao, Chenming Sun, Baojun Zhang.

Antigen-specific effector CD4+ T cells are critical for defense against exogenous pathogens. However, the epigenetic mechanisms underlying CD4+ T cell immune responses, particularly RNA modifications, remain incompletely understood. In this study, we employed a T cell-specific deletion of the fat mass and obesity-associated protein (FTO), a key N6-methyladenosine (m6A) demethylase, to elucidate its role in CD4+ T cell mediated immunity. Our findings demonstrate that FTO is essential for maintaining CD4+ T cell immune responses and protective functions. Specifically, FTO deficiency restricts the expansion of CD4+ T helper (Th)1 effector cells following antigen challenge and results in decreased expression of T-bet and IFN-γ in Th1 cells. Additionally, FTO deficient CD4+ T cells exhibit impaired pathogen elimination. Collectively, our study reveals a novel epigenetic regulatory mechanism in supporting CD4+ T cell differentiation, providing new insights into the post-transcriptional regulation of CD4+ T cell immunity and highlighting the potential for therapeutic strategies.

DOI: https://doi.org/10.1016/j.molimm.2025.05.004
Nat Neurosci. 2025 May 22.

Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration.

Janos Groh, Ruoqing Feng, Xidi Yuan, Lu Liu, Dennis Klein, Gladis Hutahaean, Elisabeth Butz, Zhen Wang, Lisa Steinbrecher, Jonas Neher, Rudolf Martini, Mikael Simons.

Aging is the major risk factor for neurodegeneration and is associated with structural and functional alterations in white matter. Myelin is particularly vulnerable to aging, resulting in white matter-associated microglia activation. Here we used pharmacological and genetic approaches to investigate microglial functions related to aging-associated changes in myelinated axons of mice. Our results reveal that maladaptive microglia activation promotes the accumulation of harmful CD8+ T cells, leading to the degeneration of myelinated axons and subsequent impairment of brain function and behavior. We characterize glial heterogeneity and aging-related changes in white matter by single-cell and spatial transcriptomics and reveal elaborate glial-immune interactions. Mechanistically, we show that the CXCL10-CXCR3 axis is crucial for the recruitment and retention of CD8+ T cells in aged white matter, where they exert pathogenic effects. Our results indicate that myelin-related microglia dysfunction promotes adaptive immune reactions in aging and identify putative targets to mitigate their detrimental impact.

DOI: https://doi.org/10.1038/s41593-025-01955-w
EMBO Mol Med. 2025 May 21.

Restricting SLC7A5-mediated Leucine uptake in T cells prevents acute GVHD and maintains GVT response.

Nieves Fernández-Gallego, Blanca Anega, Susana Luengo-Arias, Maider Bizkarguenaga, Rubén Gil-Redondo, Nieves Embade, Laura Navarrete-Arias, Marta Ramírez-Huesca, Emigdio Álvarez-Corrales, Sara G Dosil, Raquel Castillo-González, Amelia Rojas-Gomez, Inés Espeleta, Sara Martínez-Martínez, Arantzazu Alfranca, Virginia G de Yebenes, Noa Beatriz Martín-Cófreces, Julián Aragonés, Pilar Martin, Oscar Millet, Francisco Sánchez-Madrid, Danay Cibrian.

  The L-Leu amino acid transporter SLC7A5 has become an important target in inflammation and cancer. However, its role in acute graft-versus-host disease (aGVHD) and graft versus tumor (GVT) remains unexplored. We demonstrate that SLC7A5 deletion affected T cell activation, expansion and survival, and reduced IFNγ and granzyme B expression, thus controlling aGVHD, but without effect on tumor growth. On the other hand, dietary restriction of L-Leu reduced aGVHD by controlling T cell expansion, inducing apoptosis, and affecting granzyme B secretion. However, CD8 T cells did not fail to activate and express IFNγ in the absence of L-Leu, and showed an increased proportion of central memory T cells, which contributed to the GVT response. Deletion of SLC7A5 in T cells compromises mTORC1, glycolysis and mitochondrial oxidation. On the contrary, L-Leu removal reduced mTORC1 and completely blocked glycolysis but preserved mitochondrial function, favoring the generation of central memory responses and expression of stemness marker TCF1. In addition, our metabolomics data underscores the L-Leu-derived metabolite β-hydroxybutyrate as an important marker for SLC7A5-dependent allogenic T cell expansion in aGVHD.

Keywords:  Graft-versus-Host Disease; Graft-versus-Tumor; L-Leu; SLC7A5; T-Cell-Metabolism

DOI:  https://doi.org/10.1038/s44321-025-00250-2
Int Immunol. 2025 May 23. pii: dxaf028. [Epub ahead of print]

The Arf pathway is required for resolving ER stress during T cell activation.

Mami Sumiyoshi, Yui Kotani, Chikako Shimokawa, Sukhonthip Khueangchiangkhwang, Yoichi Maekawa, Yoshiyuki Matsuo, Yoshiki Yasukochi, Koichiro Higasa, Yasunori Kanaho, Toshio Watanabe, Satoshi Matsuda.

  Upon antigen recognition, T cells undergo rapid cell proliferation and differentiation, which is accompanied by a drastic change in cellular metabolism. The ADP-ribosylation factor (Arf) pathway contributes to cellular homeostasis by orchestrating vesicle trafficking, and our previous study using mice lacking both Arf1 and Arf6 (Arf-KO) revealed that Th17-mediated autoimmune diseases were markedly suppressed in Arf-KO mice though its precise mechanism remained elusive. Here, we show that Arf pathway modulates cellular metabolism in T cell activation and survival. We found that the lack of Arf1 and Arf6 resulted in hyper-activation of mTORC1, a master regulator of cellular metabolism, as well as unresolved endoplasmic reticulum (ER) stress, leading to exaggerated apoptosis during T cell activation. We further demonstrated that treatment with IL-21, a potent inducer of Tfh differentiation, rescued Arf-KO T cells from apoptosis by attenuating ER stress in vitro. Accordingly, antigen-specific antibody production and host defenses against infections such as Leishmania major or Heligmosomoides polygyrus infections were significantly preserved in Arf-KO mice. Taken together, these findings provide mechanistic insights linking the Arf pathway with T cells homeostasis during activation and identify the Arf pathway as an ideal therapeutic target for autoimmune diseases with a low risk of opportunistic infections.

Keywords:  IL-21; Tfh; mTORC1; metabolic reprogramming

DOI:  https://doi.org/10.1093/intimm/dxaf028
Aging Cell. 2025 May 21. e70100

Age-Related Oxidative Stress and Mitochondrial Dysfunction in Lymph Node Stromal Cells Limit the Peripheral T Cell Homeostatic Maintenance and Function.

Sandip Ashok Sonar, Ruchika Bhat, Heather L Thompson, Christopher P Coplen, Jennifer L Uhrlaub, Mladen Jergovic, Janko Ž Nikolich.

  Lymph nodes (LN) are the key organs in charge of long-term maintenance of naïve lymphocytes and their initial, primary activation upon infection. Accumulating evidence indicates that LN stromal cells undergo degenerative changes with aging that critically impair LN function, including the generation of protective primary immune responses. The nature of these defects remains incompletely understood. We here demonstrate that age-related LN stromal changes manifest themselves in mitochondrial dysfunction and oxidative stress. Ex vivo, all three major stromal cell subsets, fibroblastic reticular cells (FRC), lymphatic endothelial cells (LEC), and blood endothelial cells (BEC) exhibit elevated mitochondrial reactive oxygen species (ROS) stress, reduced mitochondrial potential, and elevated mitochondrial mass with aging. Old FRC also exhibited elevated cytoplasmic ROS production. This was accompanied by the reduced ability of old LN stromal cells to support Tn survival in vitro, a defect alleviated by pretreating old LN stroma with the general antioxidant N-acetyl cysteine (NAC) as well as by mitochondrial ROS-reducing (mitoquinone) and mitophagy-inducing (urolithin A) compounds. Mitochondrial dysfunction and, in particular, reduced mitochondrial potential in old FRC were also seen upon vaccination or infection in vivo. Consistent with these results, in vivo antioxidant treatment of old mice with NAC restored to adult levels the numbers of antigen-specific CD8+ effector T cells and their production of granzyme B in response to antigenic challenge.

Keywords:  T cell homeostasis; aging; lymph node stromal cells; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.1111/acel.70100
Nature. 2025 May 21.

Unravelling cysteine-deficiency-associated rapid weight loss.

Alan Varghese, Ivan Gusarov, Begoña Gamallo-Lana, Daria Dolgonos, Yatin Mankan, Ilya Shamovsky, Mydia Phan, Rebecca Jones, Maria Gomez-Jenkins, Eileen White, Rui Wang, Drew R Jones, Thales Papagiannakopoulos, Michael E Pacold, Adam C Mar, Dan R Littman, Evgeny Nudler.

Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

DOI: https://doi.org/10.1038/s41586-025-08996-y
J Transl Med. 2025 May 16. 23(1): 554

Single-cell transcriptomics reveals metabolic remodeling and functional specialization in the immune microenvironment of bone tumors.

Jun Chen, Na Cui, Shao-Hui He, Chun-Yan Xia, Wei-Qing Li.

   OBJECTIVE: To investigate the metabolic remodeling and functional specialization of immune cells within the tumor microenvironment (TME) of bone tumors, including Ewing's sarcoma, osteosarcoma, and giant cell tumor of bone, through high-resolution single-cell RNA sequencing (scRNA-seq) analysis.
METHODS: Immune cells were isolated from 13 bone tumor samples and profiled via scRNA-seq to delineate cellular compositions, metabolic adaptations, and intercellular communication networks. Differential gene expression analysis, metabolic pathway enrichment, and pseudotime trajectory inference were employed to characterize functional states and differentiation processes of immune cell subsets.
RESULTS: We identified 12 major immune cell clusters with distinct functional and metabolic characteristics. Naïve T cells exhibited amino acid metabolism-dependent activation potential, whereas NK cells relied on lipid metabolism and the TCA cycle for cytotoxic activity. Macrophage subsets demonstrated functional divergence: C06 macrophages adopted lipid metabolism to facilitate immunosuppression and tissue repair, while C04 macrophages displayed pro-inflammatory characteristics associated with complement activation. Intercellular signaling analysis revealed FN1 as a central regulator of immune coordination, governing cell adhesion, migration, and homeostasis within the TME.
CONCLUSION: This study provides novel insights into the metabolic and functional plasticity of immune cells in bone tumor TMEs, underscoring the critical role of metabolic remodeling in immune regulation. Our findings highlight potential therapeutic targets for modulating immune cell function and offering new avenues to improve treatment outcomes for patients with bone tumors.

Keywords:  Bone tumors; Immune microenvironment; Metabolic remodeling; ScRNA-seq

DOI:  https://doi.org/10.1186/s12967-025-06346-0
J Gerontol A Biol Sci Med Sci. 2025 May 20. pii: glaf112. [Epub ahead of print]

Mitochondrial bioenergetic profiling in T cell subsets associates with functional health in older adults: A cross-sectional analysis from the INSPIRE-T cohort.

Nabila Jabrane-Ferrat, Jérémy Raffin, Jordi Gouilly, Souad Najib, Anne-Laure Iscache, Catherine Marques, Julien Hall, Nathan Jolivet, Guillaume Combes, Nathalie Viguerie, Sébastien Dejean, Sophie Guyonnet, Yves Rolland, Cendrine Cabou, Bruno Vellas, Philipe de Souto Barreto, Laurent O Martinez, Hicham El Costa.

  Aging varies across individuals, highlighting the need for better markers of functional decline. This study investigates the hypothesis that T cell energy metabolism is correlated with functional health in older adults. We used flow cytometry-based profiling to examine energy metabolism, focusing on mitochondrial OXPHOS activity (MitoDep, expressed as percentage), in peripheral CD4 and CD8 T cell subsets from 187 participants aged 70-89 years (mean age 78.7 [SD 5.3], 57.7% [n = 108] women) within the Inspire-T cohort. Associations with Fried frailty phenotype were evaluated, using logistic regression. Relationships with intrinsic capacity (IC) score were assessed using partial least square regression (PLS) and piecewise linear regression models, adjusting for age, sex and comorbidities. MitoDep was significantly lower in prefrail/frail individuals (47% of the study population) across several T cells subsets. In CD4 regulatory T cell (CD4Treg) subsets, higher MitoDep was significantly associated with reduced odds of prefrailty/frailty. Piecewise regression identified a breakpoint in memory CD4Treg MitoDep at 58.5% (95% CI, 50.7-67.5). Below this threshold, reduced MitoDep was significantly associated with lower IC (β = 0.40, p = 0.0104). This study establishes a novel link between T cell mitochondrial OXPHOS activity and functional health in older adults, offering insights for improved patient stratification and personalized lifestyle or therapeutic interventions.

Keywords:  Aging; Energy metabolism; Frailty; Intrinsic capacity; T lymphocytes

DOI:  https://doi.org/10.1093/gerona/glaf112
Immunology. 2025 May 19.

Beyond Canonical Immune Checkpoints: Overexpression of TNFRSF Members 4-1BB and OX-40 Marks T Cells Exhibiting Phenotypic Features of Exhaustion in Cervical Carcinoma.

Jose Manuel Rojas-Diaz, Fabiola Solorzano-Ibarra, Nadia Tatiana Garcia-Barrientos, Ksenia Klimov-Kravtchenko, Jose Alfonso Cruz-Ramos, Marcela Sofia Guitron-Aviña, Pedro Ivan Urciaga-Gutierrez, Pablo Cesar Ortiz-Lazareno, Martha Cecilia Tellez-Bañuelos, Miriam Ruth Bueno-Topete, Jesse Haramati, Susana Del Toro-Arreola.

  T cells are pivotal in combating cancer; however, they can become exhausted during tumour progression, losing their cytotoxic capacity and upregulating inhibitory receptors including PD-1 and TIGIT. While checkpoint blockade has emerged as a potent treatment option for numerous cancers, patient selection, long-term efficacy, and adverse effects still remain an issue. For these reasons, it is important to investigate other pathways that might lead to selective reactivation of the immune system. Co-stimulatory TNFRSF receptors, including 4-1BB and OX-40, have emerged as promising targets for reactivating exhausted T cells. However, their expression on exhausted peripheral and tumour-infiltrating lymphocytes (TILs) is not well characterised, particularly in cervical cancer (CC), which remains the leading cause of gynaecological cancer mortality in low- and middle-income countries. To investigate the expression of these receptors, PBMCs were collected from CC patients and healthy donors, along with TILs from tumour biopsies, and analysed using multiparametric flow cytometry. Our findings revealed an increased population of phenotypically exhausted (PD-1+TIGIT+) CD4+ and CD8+ T cells in TILs, and, to a lesser extent, in peripheral blood and from CC patients. These exhausted T cell subsets exhibited selective overexpression of 4-1BB and OX-40 compared to phenotypically non-exhausted cells (PD-1-TIGIT-). In TILs, 4-1BB was overexpressed 12.7-fold in CD8 cells with the exhausted phenotype, OX-40 was overexpressed 3.3-fold; in CD4 cells with the exhausted phenotype, the overexpression was 7.8× and 3.8× for 4-1BB and OX-40, respectively. CD8 and CD4 T cells that were PD-1 + TIGIT+ 4-1BB+ were 7.3× and 16× more likely to be found in the tumour versus peripheral blood. Additionally, subpopulations of PD-1high T cells were significantly elevated in the tumour-infiltrating T cells and TIGIT expression was positively associated with PD-1 levels in peripheral patient CD8+ and CD4+ T cells, potentially indicating an advanced state of exhaustion. These findings suggest that TNFRSF members, especially 4-1BB, may serve as potential immunotherapeutic targets for reinvigorating exhausted T cells in CC.

Keywords:  4‐1BB; CD4+ T cell; CD8+ T cell; OX‐40; PD‐1; TIGIT; cervical cancer

DOI:  https://doi.org/10.1111/imm.13945
Sci Adv. 2025 May 23. 11(21): eadr9331

CD8+ T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells.

Phillip Schiele, Alberto Sada Japp, Regina Stark, Joanna J Sattelberg, Christos Nikolaou, Gereon Kornhuber, Parya Abbasi, Nina Ding, Stanislav Rosnev, Stefan Meinke, Kerstin Mühle, Lucie Loyal, Julian Braun, Manuela Dingeldey, Sibel Durlanik, Nadine Matzmohr, Donata Ponikwicka-Tyszko, Slawomir Wolczynski, Nafis A Rahman, Ichiro Taniuchi, Stephan Schlickeiser, Claudia Giesecke-Thiel, Thomas Blankenstein, Il-Kang Na, Andreas Thiel, Marco Frentsch.

T cells and their effector functions, in particular the canonical cytotoxicity of CD8+ T cells involving perforin, granzymes, Fas ligand (FasL), and tumor necrosis factor related apoptosis inducing ligand (TRAIL), are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8+ T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8+ T cells expressed CD40L, and conditional CD40L ablation in CD8+ T cells alone led to tumor formation. Mechanistically, CD40L+CD8+ T cells can induce cell death in CD40-expressing cancer cells by triggering caspase-8 activation. We demonstrate that a gene signature for resistance to CD40 signaling-induced cell death strongly correlates with worse survival in different human cancer cohorts. Our results introduce CD40L as a rather counterintuitive, noncanonical cytotoxic factor that complements the capabilities of CD8+ T cells to combat cancers and has the potential to enhance the efficacy of immunotherapies.

DOI: https://doi.org/10.1126/sciadv.adr9331