bims-stacyt 2025-10-05 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–10–05
thirteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

GDF15 regulates development and growth of sympathetic neurons to enhance energy expenditure and thermogenesis.
GCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling.
HIF-2α-Driven Lipogenesis and Inflammation in MASLD: Role of ATF4 Signaling.
Correlation of growth differentiation factor 15 level in esophageal cancer with cachectic indicators and postoperative infectious complication.
Cancer-Associated Fibroblast-Derived GDF15 Induces Oxidative Stress and Neutrophil Infiltration in Head and Neck Squamous Cell Carcinoma through the PI3K/AKT/STAT3 Axis Cascade.
ER stress sensor PERK promotes T-cell pathogenicity in GVHD by regulating ER-associated degradation.
Targeting the hypoxia signaling pathway with nanomedicine to reverse immunotherapy resistance.
Activin receptor type IIA/IIB blockade increases muscle mass and strength, but compromises glycemic control in mice.
ER stress tolerance is regulated by copper-dependent PERK kinase activity.
Dietary methionine restriction primes T cell metabolism for activation and tumor inhibition and enhances the efficacy of immune checkpoint blockade.
Codon-specific ribosome stalling reshapes translational dynamics during branched-chain amino acid starvation.
Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.
Proteotoxic stress response drives T cell exhaustion and immune evasion.

Exp Mol Med. 2025 Oct 01.

GDF15 regulates development and growth of sympathetic neurons to enhance energy expenditure and thermogenesis.

Jinyoung Kim, Annie Zhao, Seo Hyun Park, Jaeseok Han, Deok-Hyeon Cheon, Sang-Hyeon Ju, Yoonhyuk Jang, Kon Chu, Hyung Jin Choi, Jiyoon Kim, Myung-Shik Lee.

Growth differentiation factor 15 (GDF15) induces weight loss and increases sympathetic activity through its receptor GFRAL. Given that RET, a GFRAL coreceptor, influences neuronal growth, we studied whether GDF15 can induce the development or growth of sympathetic neurons, in addition to its effect on sympathetic activity. Here we we used GDF15-transgenic and Gdf15-knockout mice to explore the role of GDF15 in the development and activity of sympathetic neurons. GDF15-transgenic mice exhibited increased surface area and volume of sympathetic neurite in adipose tissues. Furthermore, these mice showed heightened energy expenditure, thermogenesis, cold tolerance and an elevated sympathetic response to hypoglycemia. GFRAL was expressed in sympathetic ganglion cells, which was enhanced by GDF15. RET and its downstream signaling molecules such as AKT, ERK and CREB were activated in the sympathetic ganglia by transgenic expression of GDF15 in vivo or treatment with GDF15 in vitro, an leading to increased expression of genes related to thermogenesis, neurite growth or extension and catecholamine synthesis. An ex vivo treatment of sympathetic ganglia with GDF15 also promoted neurite growth and extension. By contrast, Gdf15-knockout mice showed opposite phenotypes, underscoring the physiological role of GDF15 in the development and activity of the sympathetic nervous system. These findings indicate that GDF15 regulates not only the sympathetic activity but also the development or growth of sympathetic neurons through GFRAL expressed in sympathetic ganglion cells, which could contribute to energy expenditure and weight loss. The modulation of GDF15 could be a therapeutic option against diseases or conditions associated with dysregulated sympathetic activity.

DOI: https://doi.org/10.1038/s12276-025-01543-9
Science. 2025 Oct 02. 390(6768): eads8728

GCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling.

Changqian Zhou, Miao Zhang, Jason Murray, Joao Paulo, Steve Gygi, Sichen Shao, Malcolm Whitman, Tracy Keller.

During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stresses. GCN2 activation has been linked to its association with uncharged tRNAs, specific ribosomal proteins, and conditions of translational arrest, but their relative contribution to activation is unclear. Here, we used in vitro translation to reconstitute GCN2 activation by amino acid stress and compared collided ribosome populations induced by diverse translational stressors. Initiation of GCN2 signaling required the di-ribosome sensor GCN1, which recruits GCN2 to ribosomes in a collision-dependent manner, where GCN2 becomes activated by key ribosomal interactions and stably associated with collided ribosomes. Our findings define the molecular requirements and dynamics of GCN2 activation.

DOI: https://doi.org/10.1126/science.ads8728
Cell Mol Gastroenterol Hepatol. 2025 Sep 29. pii: S2352-345X(25)00192-4. [Epub ahead of print] 101651

HIF-2α-Driven Lipogenesis and Inflammation in MASLD: Role of ATF4 Signaling.

Zhe Yang, Niujian Wu, Xin Li, Yun Li, Zhanjin Lu, Taoping Sun, Zhixing Cao, Xianghong Wang, Chen Yang, Shisong Han, Hongyun Lu.

   BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an imbalance of lipid metabolism and chronic inflammation. Emerging evidence suggests a role for Hypoxia-inducible Factor 2α (HIF-2α) in MASLD progression. However, the mechanistic linkage between HIF-2α and steatohepatitis progression remains largely elusive.
METHODS: Here, hepatocyte-specific HIF-2α knockout mice were used to investigate the pathophysiological role of HIF-2α in MASLD. Multiple gain- and loss-of-function experiments in primary hepatocytes and established human hepatocyte cell lines were performed to elucidate the molecular mechanisms by which HIF-2α contributes to MASLD progression.
RESULTS: Compared to their wild-type littermates, hepatocyte-specific HIF-2α knockout mice exhibited a substantial reduction in HFD-induced hepatic steatosis and inflammatory signaling. Furthermore, HIF-2ɑ deficiency in primary hepatocytes and both L02 and MIHA cell lines markedly inhibited the lipid accumulation, inflammation, and endoplasmic reticulum stress in vitro upon FFAs challenge. Mechanistically, HIF-2 directly bound to the promoter region of protein kinase RNA-like ER kinase (PERK), leading to the activation of the activating transcription Factor 4 (ATF4) signaling under metabolic stress, thereby aggravating lipogenesis while inhibiting lipid oxidation in hepatocytes.
CONCLUSION: These data indicate that HIF-2α acts as a contributing factor to MASLD progression via ATF4 signaling.

Keywords:  Activating transcription Factor 4; Hypoxia-inducible Factor 2α; Inflammation; Lipid homeostasis; MASLD

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101651
Esophagus. 2025 Sep 29.

Correlation of growth differentiation factor 15 level in esophageal cancer with cachectic indicators and postoperative infectious complication.

Yohei Ozawa, Hiroshi Okamoto, Yusuke Taniyama, Chiaki Sato, Hirotaka Ishida, Takeya Sato, Shinobu Ohnuma, Michiaki Unno, Takaaki Abe, Takashi Kamei.

   BACKGROUND: Patients with esophageal cancer (EC) usually have multiple comorbidities, particularly, high cachexia incidence, which may lead to increased postoperative complications. A novel inflammatory marker, growth differentiation factor 15 (GDF15), was recently reported to be associated with cancer cachexia. This study evaluated the correlation between clinical data suggestive of cachexia in patients with EC and circulating GDF15 levels.
METHODS: Eighty patients with EC were enrolled in this study. Plasma samples were collected before initiating any cancer treatment. GDF15 was quantified using ELISA. Clinical information, including age, comorbidities, biochemical data, Controlling Nutritional Status score, and Psoas muscle index (PMI), was collected from the clinical records. Clinical impact of GDF15 was then evaluated and compared with cachectic indicators or postoperative results.
RESULTS: The median value of GDF15 was 1168 pg/mL (range 298-9100 pg/mL). GDF15 values statistically correlated with age, prevalence of diabetes, serum level of aspartate aminotransferase/γ-glutamyltransferase/creatinine/blood sugar/albumin, and PMI. Sixty-three patients finally underwent curative esophagectomy with right thoracic approach and gastric tube reconstruction. Patients with infectious complications had a statistically higher GDF15 than those without. The cut-off value was 930 pg/mL for detecting infectious complications, with an area under the receiver operating characteristic curve value of 0.685, and high GDF15 was detected as an independent risk factor for postoperative infectious complications.
CONCLUSIONS: GDF15 is potentially suggestive of general condition deterioration from aging, organ dysfunction, and decreased muscle mass, which may lead to cachexia in patients with EC. Moreover, patients with higher GDF15 are at a risk of postoperative infectious complications.

Keywords:  Cachexia; Esophageal cancer; GDF-15; Malnutrition; Sarcopenia

DOI:  https://doi.org/10.1007/s10388-025-01157-0
Research (Wash D C). 2025 ;8 0901

Cancer-Associated Fibroblast-Derived GDF15 Induces Oxidative Stress and Neutrophil Infiltration in Head and Neck Squamous Cell Carcinoma through the PI3K/AKT/STAT3 Axis Cascade.

Zhijie Zhao, Huabao Cai, Zhenzhen Zhao, Xiaojing Wang, Wenyang Nie, Fu Zhao, Yisheng Chen, Yanyu Ding, Zhiwen Luo, Zhiheng Lin, Yantao Ding.

Background: Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor of the oral mucosal epithelium. The high incidence of recurrence and metastasis presents substantial challenges for treatment, underscoring the complex molecular landscape underlying the disease. The purpose of this work is to clarify how HNSCC tumor cells and cancer-associated fibroblasts (CAFs) interact. Methods: Spatial transcriptome sequencing and single-cell RNA sequencing had been employed to describe the biological characteristics of CAFs in HNSCC. The biological connection between CAFs and tumor cells was verified by molecular interaction experiments. In addition, the regulatory effect of CAFs on oxidative stress in tumor cells and the phenotypic conversion of neutrophils were explored through a coculture system, a knockdown/overexpression method, flow cytometry, and animal experiments. Finally, potential small-molecule inhibitors were screened by molecular dynamics simulation and validated through in vitro and in vivo assays. Results: Growth differentiation factor 15 (GDF15) promoted tumor cell growth and invasion by enhancing PCNA clamp associated factor (PCLAF) transcription through interferon regulatory factor 5 modulation. Its interaction with the receptor GDNF family receptor alpha like (GFRAL) triggered chronic inflammatory signaling via the phosphatidylinositol-3 kinase/protein kinase b/signal transducer and activator of transcription 3 pathway, which led to oxidative stress imbalance and contributed to tumor progression and the development of drug resistance. Moreover, GDF15 activated the extracellular signal-regulated kinase 1/2 pathway through tumor necrosis factor-α, thereby facilitating neutrophil infiltration and promoting lung metastasis in HNSCC. Notably, risperidone (SM-2) emerged as a potential inhibitory regulator capable of disrupting the cascade effects mediated by the GDF15-GFRAL axis, underscoring its therapeutic relevance. Conclusion: This study identifies the GDF15-GFRAL signaling axis as a critical regulator of oxidative stress and immune evasion in HNSCC and demonstrates that the novel small-molecule SM-2 effectively targets this pathway, highlighting its potential as a promising therapeutic strategy.

DOI: https://doi.org/10.34133/research.0901
J Clin Invest. 2025 Sep 30. pii: e190958. [Epub ahead of print]

ER stress sensor PERK promotes T-cell pathogenicity in GVHD by regulating ER-associated degradation.

Qiao Cheng, Hee-Jin Choi, Yongxia Wu, Xiaohong Yuan, Allison Pugel, Linlu Tian, Michael Hendrix, Denggang Fu, Reza Alimohammadi, Chen Liu, Xue-Zhong Yu.

  Endoplasmic reticulum (ER) stress through IRE1/XBP-1 is implicated in the onset and progression of graft-versus-host disease (GVHD), but the role of ER stress sensor PERK in T-cell allogeneic responses and GVHD remains unexplored. Here, we report that PERK is a key regulator in T-cell allogeneic response and GVHD induction. PERK augments GVHD through increasing Th1 and Th17 population, while reducing Treg differentiation by activating Nrf2 pathway. Genetical deletion or selective inhibition of PERK pharmacologically reduces GVHD while preserving graft-versus-leukemia (GVL) activity. At cellular level, PERK positively regulates CD4+ T-cell pathogenicity, while negatively regulating CD8+ T-cell pathogenicity in the induction of GVHD. At molecular level, PERK interacts with SEL1L and regulates SEL1L expression, leading to augmented T-cell allogeneic responses and GVHD development. In vivo, PERK deficiency in donor T cells alleviate GVHD through ER-associated degradation (ERAD). Furthermore, pharmacological inhibition of PERK with AMG44 significantly suppresses the severity of GVHD induced by murine or human T cells. In summary, our findings validate PERK as a potential therapeutic target for the prevention of GVHD while preserving GVL responses, and uncover the mechanism by which PERK differentially regulates CD4+ versus CD8+ T-cell allogeneic and anti-tumor responses.

Keywords:  Bone marrow transplantation; Immunology; Inflammation

DOI:  https://doi.org/10.1172/JCI190958
Cancer Drug Resist. 2025 ;8 46

Targeting the hypoxia signaling pathway with nanomedicine to reverse immunotherapy resistance.

Xiaoliang Cheng, Peixing Wang, Hongqiang Lyu, Yonghyun Lee, Juyoung Yoon, Haiyan Dong.

  Immunotherapy has emerged as a major therapeutic strategy for cancer; however, immunotherapy resistance remains a significant challenge. Hypoxia, a key hallmark of the tumor microenvironment resulting from the imbalance between the high oxygen demand of rapidly proliferating cancer cells and the limited supply from abnormal blood vessels, plays a central role in driving immunotherapy resistance. Hypoxia-inducible factor-1α (HIF-1α) and its downstream signaling pathways contribute to this resistance by promoting macrophage polarization toward the protumorigenic M2 phenotype, inducing T cell exhaustion, facilitating immune evasion, enhancing angiogenesis, and activating other resistance mechanisms. The review highlights the mechanisms by which hypoxia regulates resistance to immunotherapy and provides a comprehensive overview of nanotechnology-based strategies designed to counteract hypoxia-induced resistance. Finally, the prospects and challenges of translating nanomedicine-based drug delivery systems into clinical practice for overcoming immunotherapy resistance are outlined.

Keywords:  HIF-1α; Immunotherapy resistance; T cell exhaustion; immune evasion; nanomedicine; tumor-associated macrophages; vascular normalization

DOI:  https://doi.org/10.20517/cdr.2025.132
Mol Metab. 2025 Sep 27. pii: S2212-8778(25)00168-1. [Epub ahead of print] 102261

Activin receptor type IIA/IIB blockade increases muscle mass and strength, but compromises glycemic control in mice.

Michala Carlsson, Emma Frank, Joan M Màrmol, Mona Sadek Ali, Steffen H Raun, Edmund Battey, Nicoline Resen Andersen, Andrea Irazoki, Camilla Lund, Carlos Henríquez-Olguin, Martina Kubec Højfeldt, Pauline Blomquist, Frederik Duch Bromer, Gabriele Mocciaro, Andreas Lodber, Christian Brix Folsted Andersen, Marco Eijken, Andreas Mæchel Fritzen, Jonas Roland Knudsen, Erik A Richter, Lykke Sylow.

   PURPOSE: Blocking the Activin receptor type IIA and B (ActRIIA/IIB) has clinical potential to increase muscle mass and improve glycemic control in obesity, cancer, and aging. However, the impact of blocking ActRIIA/IIB on strength, metabolic regulation, and insulin action remains unclear.
METHODS: Here, we investigated the effect of short- (10mg kg-1 bw, once, 40h) or long-term (10mg kg-1 bw, twice weekly, 21 days) antibody treatment targeting ActRIIA/IIB (αActRIIA/IIB) in lean and diet-induced obese mice and engineered human muscle tissue.
RESULTS: Short-term ActRIIA/IIB administration in lean mice increased insulin-stimulated glucose uptake in skeletal muscle by 76-105%. Despite this, ActRIIA/IIB-treated mice exhibited 33% elevated blood glucose and glucose intolerance. Long-term αActRIIA/IIB treatment increased muscle mass (+20%) and reduced fat mass (-8%) in obese mice but failed to enhance insulin-stimulated glucose uptake in muscle or adipose tissue. Instead, it induced glucose intolerance, cardiac hypertrophy with glycogen accumulation, and elevated hepatic triacylglycerol and glucose output in response to pyruvate. Concomitantly, long-term ActRIIA/IIB treatment increased strength (30%) in mouse soleus muscle and prevented activin A-induced loss of tissue strength in engineered human muscle tissue. Surprisingly, long-term ActRIIA/IIB treatment lowered volitional running (-250%).
CONCLUSION: Our findings demonstrate that, in accordance with human studies, ActRIIA/IIB blockade holds promise for increasing muscle mass, strength, and muscle insulin sensitivity. However, contrary to the improved glycemic control in humans, ActRIIA/IIB blockade in mice causes severe glucose intolerance and lowers voluntary physical activity. Our study underscores the complex metabolic and functional consequences of ActRIIA/IIB blockade, and highlight species differences on glycemic control, which warrant further investigation.

Keywords:  Activin receptor; Bimagrumab; Insulin resistance; Obesity; glycemic regulation; muscle mass

DOI:  https://doi.org/10.1016/j.molmet.2025.102261
Cell Rep. 2025 Sep 25. pii: S2211-1247(25)01089-7. [Epub ahead of print]44(10): 116318

ER stress tolerance is regulated by copper-dependent PERK kinase activity.

Sarah E Bond Newton, Xinglong Shi, Noah R Beratan, Julia Perhacs, Jitendra K Arya, Margaret K Bond, Tali Gidalevitz, Cagla Akay-Espinoza, Donita C Brady, Kelly L Jordan-Sciutto.

  Pancreatic/PKR-like endoplasmic reticulum (ER) kinase (PERK) is a kinase that, in response to ER stress, mediates dual homeostatic and pro-apoptotic signaling. Thus, intricate regulation is required for physiological function. Attempts to modulate PERK activity have shown that the determinants of adaptive vs. maladaptive signaling remain ambiguous. Here, with purified protein, we provide evidence that PERK binds copper, identifies residues required for interaction, and demonstrates that copper is necessary for kinase activity. Furthermore, cellular PERK activity can be modulated via copper availability, and this regulatory relationship can be manipulated to dictate ER stress tolerance. Critically, these phenomena translate to phenotypes in vivo, as C. elegans harboring a "PERK-copper mutant" exhibit exacerbated ER-stress sensitivity. The copper-PERK paradigm suggests that copper homeostasis, as a regulator of PERK, may constitute a critical factor in resolving the long-standing ambiguity in endeavors to therapeutically target PERK.

Keywords:  CP: Cell biology; ER stress; ISR; PERK; UPR; copper; kinase regulation; stress tolerance

DOI:  https://doi.org/10.1016/j.celrep.2025.116318
bioRxiv. 2025 Sep 23. pii: 2025.09.18.676961. [Epub ahead of print]

Dietary methionine restriction primes T cell metabolism for activation and tumor inhibition and enhances the efficacy of immune checkpoint blockade.

Xiaoqing Qing, Binita Chakraborty, Panpan Liu, Sandeep Artham, Patrick K Juras, Dongyin Guan, Kristen E Pauken, Ching-Yi Chang, Xia Gao.

The proliferation of many cancer cells is methionine dependent and dietary methionine restriction (MR) has shown anti-tumor effects in a wide variety of immunodeficiency preclinical models. Yet, whether MR exerts an anti-tumor effect in the presence of an immune-competent background remains inconclusive. Accumulating evidence has shown an essential role of methionine in immune cell differentiation and function. Thus, competition for methionine between tumor cells and immune cells in the tumor microenvironment may drive tumor growth and tumor response to therapy. Here, we aim to define the impact of MR on tumor growth and associated immunity. We first assessed the effect of MR in a series of immunocompetent mouse models of melanoma, colorectal cancer, breast cancer, and lung. MR led to a broad tumor inhibition effect across these models and such tumor inhibition was not sex-or genetic background-dependent but appears to be fully or partially immune-dependent. Through flow cytometry analysis, we found a consistent increase in intratumoral activated CD8 + T cells across different tumor models and depletion of CD8 + T cells partially or completely reversed MR-induced tumor inhibition in a model dependent manner. Interestingly in young healthy non-tumor-bearing mice, MR increased spleen CD3 + and CD8 + T cell populations. Metabolomics and RNAseq analysis of spleen-derived CD8 + T cells revealed significant increase in purine metabolism and amino acid metabolism and that are in line with the metabolic feature of activated T cells. Furthermore, MR improved the efficacy of anti-PD1 immune checkpoint blockade. Together, MR primes T cell metabolism for its anti-tumor effect and improves the efficacy of anti-PD1 checkpoint blockade.

DOI: https://doi.org/10.1101/2025.09.18.676961
Genome Biol. 2025 Sep 27. 26(1): 315

Codon-specific ribosome stalling reshapes translational dynamics during branched-chain amino acid starvation.

Lina Worpenberg, Cédric Gobet, Felix Naef.

   BACKGROUND: Cells regulate protein synthesis in response to fluctuating nutrient availability through mechanisms that affect both translation initiation and elongation. Branched-chain amino acids, leucine, isoleucine, and valine, are essential nutrients. However, how their depletion affects translation remains largely unclear. Here, we investigate the immediate effects of single, double, and triple branched-chain amino acid deprivation on translational dynamics in NIH3T3 cells using RNA-seq and ribosome profiling.
RESULTS: All starvation conditions increased ribosome dwell times, with pronounced stalling at all valine codons during valine and triple starvation, whereas leucine and isoleucine starvation produced milder, codon-specific effects. Notably, stalling under isoleucine deprivation largely decreased under triple starvation. Positional enrichment of valine codons near the 5' end and downstream isoleucine codons potentially contributes to these patterns, suggesting a possible elongation bottleneck that influences translational responses under branched-chain amino acid starvation. The presence of multiple valine stalling sites was associated with decreased protein levels. Finally, codon-specific dwell time changes correlated strongly with patterns of tRNA isoacceptor charging.
CONCLUSIONS: Together, these findings suggest that differential ribosome stalling under branched-chain amino acid starvation reflects a balance between amino acid supply, tRNA charging dynamics, codon position, and stress-response signaling.

Keywords:  Amino acid starvation; Codon-specific stalling; Elongation bottleneck; Nutrient stress response; Ribosome profiling; Translation regulation; tRNA charging

DOI:  https://doi.org/10.1186/s13059-025-03800-6
Nature. 2025 Oct 01.

Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.

Fangtao Chi, Qiming Zhang, Jessica E S Shay, Shixun Han, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Samuel Block, Sumeet Solanki, Yatrik M Shah, Matthew G Vander Heiden, Judith Agudo, Ömer H Yilmaz.

A fundamental question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues1-8. The mammalian small intestine is maintained by rapidly renewing LGR5+ intestinal stem cells (ISCs) that respond to macronutrient changes such as fasting regimens and obesogenic diets, yet how specific amino acids control ISC function during homeostasis and injury remains unclear. Here we demonstrate that dietary cysteine, a semi-essential amino acid, enhances ISC-mediated intestinal regeneration following injury. Cysteine contributes to coenzyme A (CoA) biosynthesis in intestinal epithelial cells, which promotes expansion of intraepithelial CD8αβ+ T cells and their production of interleukin-22 (IL-22). This enhanced IL-22 signalling directly augments ISC reparative capacity after injury. The mechanistic involvement of the pathway in driving the effects of cysteine is demonstrated by several findings: CoA supplementation recapitulates cysteine effects, epithelial-specific loss of the cystine transporter SLC7A11 blocks the response, and mice with CD8αβ+ T cells lacking IL-22 or a depletion of CD8αβ+ T cells fail to show enhanced regeneration despite cysteine treatment. These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.

DOI: https://doi.org/10.1038/s41586-025-09589-5
Nature. 2025 Oct 01.

Proteotoxic stress response drives T cell exhaustion and immune evasion.

Yi Wang, Anjun Ma, No-Joon Song, Ariana E Shannon, Yaa S Amankwah, Xingyu Chen, Weidong Wu, Ziyu Wang, Abbey A Saadey, Amir Yousif, Gautam Ghosh, Jay K Mandula, Maria Velegraki, Tong Xiao, Haitao Wen, Stanley Ching-Cheng Huang, Ruoning Wang, Christian M Beusch, Abdelhameed S Dawood, David E Gordon, Mohamed S Abdel-Hakeem, Hazem E Ghoneim, Gang Xin, Brian C Searle, Zihai Li.

Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies1-4. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8+ exhausted T (Tex) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (Teff) and Tex cells. We identify a distinct proteotoxic stress response (PSR) in Tex cells, which we term Tex-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis5,6, Tex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. Tex-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert Teff cells to Tex cells, and we link Tex-PSR mechanistically to persistent AKT signalling. Finally, disruption of Tex-PSR-associated chaperones in CD8+ T cells improves cancer immunotherapy in preclinical models. Moreover, a high Tex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that Tex-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41586-025-09539-1