bims-stacyt 2025-09-14 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–09–14
fourteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Early adipose tissue wasting in a preclinical model of human lung cancer cachexia.
Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
Pro-Fibrotic Immune Cells and Fibro-Adipogenic Progenitors Contribute to Skeletal Muscle Extracellular Matrix Remodeling and Fibrosis in Cancer Cachexia.
Loss of Skeletal Muscle Mass Is Associated With Reduced Cytotoxic T Cell Abundance and Poor Survival in Advanced Lung Cancer.
Glucose restriction: double edged sword in cancer treatment.
Targeting IL-6 receptor mediated metabolic pathways to control Th17 cell differentiation and inflammatory responses.
Multi-omic analysis reveals a key BCAT1 role in mTOR activation by B-cell receptor and TLR9.
Activation of the PERK/MANF/STAT3 Pathway in Astrocytes Promotes Synaptic Remodeling and Neurological Recovery in the Acute Phase After Stroke in Mice.
Targeting Cancer Translational Plasticity: IRES-Driven Metabolism and Survival Within the Tumor Microenvironment.
Modulation of fibronectin extracellular matrix enhances anti-tumor efficacy of immune checkpoint blockade.
Inherent single-cell heterogeneity of the transcriptional response to hypoxia in cancer cells.
Contribution of metabolism-independent glucose sensing to metabolic homeostasis.
The hexosamine biosynthetic pathway drives tumor immune evasion via translational control of PD-L1 at the elongation level.
TGFβ induces excessive pulmonary IL-6 secretion in cystic fibrosis via PI3K.

Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01049-6. [Epub ahead of print]44(9): 116278

Early adipose tissue wasting in a preclinical model of human lung cancer cachexia.

Deena B Snoke, Jos L van der Velden, Emma R Bellafleur, Jacob S Dearborn, Sean M Lenahan, Alexandra E Beal, Reem Aboushousha, Skyler C J Heininger, Jennifer L Ather, Madeleine M Mank, Hailey Sarausky, Daniel Stephenson, Julie A Reisz, Angelo D'Alessandro, Devdoot Majumdar, Thomas P Ahern, Kaiwen Xu, Kim L Sandler, Bennett A Landman, Yvonne M W Janssen-Heininger, Matthew E Poynter, David J Seward, Michael J Toth.

  Cancer cachexia (CC), a syndrome of skeletal muscle and adipose wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between preclinical models and human CC. To address the need for clinically relevant models of lung CC, we generated inducible, lung epithelial cell-specific KrasG12D/+ (G12D) mice. G12D mice develop CC over a protracted time course and phenocopy tissue and tumor, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. G12D mice demonstrate early loss of adipose, a phenotype that was apparent across numerous models of CC and translates to patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in CC, and adipose wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and highlight a role for early tumor metabolic reprogramming of adipose tissue in CC.

Keywords:  CP: Cancer; CP: Metabolism; inflammation; lipolysis; lung neoplasms; organoids; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2025.116278
EMBO J. 2025 Sep 08.

Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.

Amanda L Gunawan, Irene Liparulo, Andreas Stahl.

  A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.

Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis

DOI:  https://doi.org/10.1038/s44318-025-00549-3
Am J Physiol Cell Physiol. 2025 Sep 10.

Pro-Fibrotic Immune Cells and Fibro-Adipogenic Progenitors Contribute to Skeletal Muscle Extracellular Matrix Remodeling and Fibrosis in Cancer Cachexia.

Thomas D Cardaci, Arianna V Bastian, Kasie Roark, Brooke M Bullard, Mitchell M NeSmith, Christian A Unger, Robert L Price, Jason L Kubinak, E Angela Murphy, Brandon N VanderVeen.

  Cachexia, the loss of skeletal muscle mass and function with cancer, contributes to reduced life quality and worsened survival. Skeletal muscle fibrosis leads to disproportionate muscle weakness; however, the role of infiltrating immune cells and fibro-adipogenic progenitors (FAPs) in cancer-induced muscle fibrosis is not well understood. Using the C26 model of cancer cachexia, we sought to examine the changes to skeletal muscle immune cells and FAPs which contribute to excessive extracellular matrix (ECM) collagen deposition. CD2F1 male mice (n=35) were implanted with either 106 C26 or CT-26 (weight stable; WS) cells. Skeletal muscle immune cell populations, satellite cells, and FAPs were examined using high-dimensional flow cytometry. Skeletal muscle ECM ultrastructure was assessed via scanning electron microscopy (SEM) of decellularized muscle along with transmission electron microscopy (TEM). Cachectic mice had significant decreases in body weight (-13.4%, p=0.003) and skeletal muscle mass (-37%, p=0.006). Cachectic mice had elevated CD45+CD11b+Ly6g+ neutrophils compared to non-tumor bearing controls (128%, p=0.016) and elevated CD45+CD11b+Ly6g-F480+CD206+MHCII- profibrotic macrophages and increased CD45-Sca1+CD106+CD140a+ FAPs compared to WS (43%, p=0.014) and controls (59%, p=0.002) with thickening of the ECM, particularly of the endomysium and perimysium. SEM and TEM analysis also identified clusters of infiltrating cells localized to regions of excessive ECM deposition in cachectic mice that were absent in WS and controls. These data highlight changes to the muscle microenvironment which contribute to fibrosis and excessive ECM deposition in cancer cachexia. Targeting pro-fibrotic immune cells may represent a promising therapeutic approach to mitigate muscle wasting and dysfunction with cachexia.

Keywords:  FAPs; atrophy; macrophages; muscle wasting; weakness

DOI:  https://doi.org/10.1152/ajpcell.00448.2025
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70063

Loss of Skeletal Muscle Mass Is Associated With Reduced Cytotoxic T Cell Abundance and Poor Survival in Advanced Lung Cancer.

Xin Nie, Yan Sun, David P J van Dijk, Min Deng, Ralph Brecheisen, Zhaoqi Wang, Qingxin Xia, Steven M W Olde Damink, Sander S Rensen.

   BACKGROUND: Body composition alterations such as skeletal muscle (SM) loss in cancer patients are associated with poor survival. In turn, immune cell-driven pathways have been linked to muscle wasting. We aimed to investigate the relationship between body composition, tumour-infiltrating lymphocytes and survival in patients with advanced lung cancer.
METHODS: We studied 200 patients with advanced lung cancer receiving immunotherapy (n = 81) or non-immunotherapy regimens (n = 119). Body composition including SM index (SMI) at baseline and longitudinal changes were assessed using computed tomography (CT) scans at the third lumbar vertebra. Associations between body composition parameters and overall survival (OS) were evaluated using Cox regression analysis. The median value of SMI, stratified by sex, was used as the cut-off to define groups with high and low baseline SMI. Stable SMI was defined by any increase or < 2% decrease per 100 days; loss of SMI was defined by ≥ 2% decrease per 100 days. Logistic regression analysis was applied to investigate the association between SMI and peripheral circulating immune cells. Tumour-infiltrating lymphocytes were identified by immunohistochemistry, and their relationship with SMI was evaluated.
RESULTS: SMI loss was associated with shorter OS (whole cohort: HR = 2.314, 95% CI = 1.388-3.858, p = 0.001; immunotherapy cohort: HR = 3.028, 95% CI = 1.113-8.236, p = 0.03; non-immunotherapy cohort: HR = 2.298, 95% CI = 1.191-4.435, p = 0.013). Low baseline SMI was associated with higher CD3+ T cell abundance (OR = 1.240, 95% CI = 1.080-1.424, p = 0.002) but lower CD3+ CD8+ T cell abundance (OR = 0.862, 95% CI = 0.762-0.974, p = 0.018) in peripheral blood. Subsequent SMI loss during treatment was also significantly associated with higher CD3+ T cell counts (OR = 3.414, 95% CI = 1.301-8.961, p = 0.013) and lower CD3+ CD8+ T cell abundance (OR = 0.666, 95% CI = 0.459-0.968, p = 0.033). Patients with stable SMI had a higher number of CD8+ tumour-infiltrating lymphocytes than patients with SMI loss (15.4% vs. 7.9%, p = 0.036).
CONCLUSION: SM loss is an independent predictor for survival in patients with advanced lung cancer and is associated with reduced peripheral and tumour-infiltrating cytotoxic T cell abundance. An inadequate antitumour immune response may contribute to metabolic tissue wasting in cancer.

Keywords:  TILs; cytotoxic T cell; lung cancer; skeletal muscle mass; survival

DOI:  https://doi.org/10.1002/jcsm.70063
Trends Cancer. 2025 Sep 05. pii: S2405-8033(25)00210-9. [Epub ahead of print]

Glucose restriction: double edged sword in cancer treatment.

Shenglong Xia, Dingjiacheng Jia.

  Glucose restriction generally limits tumor growth. Recently, Wu et al. reported that glucose restriction inhibits primary tumors but promotes lung metastasis by forming a macrophage-dominated, natural killer (NK) cell-deficient pre-metastatic niche (PMN). This finding provides a new perspective on understanding the dual role of glucose metabolism regulation in cancer treatment.

Keywords:  cancer metastasis; exosomal TRAIL; low-carbohydrate diet; macrophages; natural killer cells; pre-metastatic niche

DOI:  https://doi.org/10.1016/j.trecan.2025.08.012
Front Immunol. 2025 ;16 1568514

Targeting IL-6 receptor mediated metabolic pathways to control Th17 cell differentiation and inflammatory responses.

Yazan Alwarawrah, Amanda G Nichols, Isha Patel, Andréa B Ball, Nancie J MacIver.

  Interleukin-6 (IL-6) is a multifunctional cytokine that plays important roles in inflammation. Several studies have shown that IL-6 regulates various aspects of T cell function, including the differentiation of CD4+ T cells into the pro-inflammatory Th17 subset. Given the tight link between T cell metabolism and function, and the role of IL-6 in regulating cellular metabolism across tissues, we investigated the role of IL-6 signaling in Th17 cell metabolism. Using T cell specific IL-6 receptor (IL-6R) conditional knockout mice and littermate controls, we found that IL-6R signaling regulates the proportions of CD4+ and CD8+ T cells and drives CD4+ T cell differentiation into Th17 cells. We also found that IL-6R signaling is required for Th17 cell glycolytic metabolism. In T cell-specific IL-6R knockout mice, Th17 cells had reduced glucose uptake and glycolysis, as well as decreased expression of key glycolytic enzymes, while showing increased basal oxygen consumption. However, we also found that IL-6R signaling enhanced oxidative capacity and mitochondrial coupling efficiency in Th17 T cells. Importantly, inhibition of lactate dehydrogenase using FX11 selectively impaired Th17 cell differentiation with minimal effects on Treg cells. These findings suggest that targeting metabolic pathways regulated by IL-6R signaling can selectively inhibit inflammatory Th17 responses, offering a potential strategy for controlling IL-6 mediated inflammation.

Keywords:  T cells; Th17; cellular metabolism; glycolysis; immunometabolism; inflammation; interleukin-6 (IL-6)

DOI:  https://doi.org/10.3389/fimmu.2025.1568514
J Clin Invest. 2025 Sep 09. pii: e186258. [Epub ahead of print]

Multi-omic analysis reveals a key BCAT1 role in mTOR activation by B-cell receptor and TLR9.

Rui Guo, Yizhe Sun, Matthew Y Lim, Hardik Shah, Joao A Paulo, Rahaman A Ahmed, Weixing Li, Yuchen Zhang, Haopeng Yang, Liang Wei Wang, Daniel Strebinger, Nicholas A Smith, Meng Li, Merrin Man Long Leong, Michael Lutchenkov, Jin-Hua Liang, Zhixuan Li, Yin Wang, Rishi Puri, Ari Melnick, Michael R Green, John M Asara, Adonia E Papathanassiu, Duane R Wesemann, Steven P Gygi, Vamsi K Mootha, Benjamin E Gewurz.

  B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states highly induced the transaminase branched chain amino acid transaminase 1 (BCAT1), which localized to lysosomal membranes to support branched chain amino acid synthesis and mechanistic target of rapamycin complex 1 (mTORC1) activation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes and identify BCAT1 as an activated B-cell therapeutic target.

Keywords:  Adaptive immunity; Amino acid metabolism; Cell biology; Lymphomas; Metabolism

DOI:  https://doi.org/10.1172/JCI186258
Neural Plast. 2025 ;2025 6776608

Activation of the PERK/MANF/STAT3 Pathway in Astrocytes Promotes Synaptic Remodeling and Neurological Recovery in the Acute Phase After Stroke in Mice.

Yashu Sun, Lan Luo, XiaoYan Li, Bing Zhang.

  Astrocytes play a crucial role in ensuring neuronal survival and function. In stroke, astrocytes trigger the unfolded protein response (UPR) to restore endoplasmic reticulum homeostasis. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a newly identified endoplasmic reticulum stress-induced neurotrophic factor, attenuates cerebral ischemic injury by reducing inflammatory responses. The mechanisms by which astrocytes regulate MANF expression and the role of MANF in modulating inflammation remain to be elucidated. In this study, we constructed middle cerebral artery occlusion (MCAO)/reperfusion model in C57BL/6J mice and an oxygen glucose deprivation/reoxygenation model in a neuronal and astrocyte coculture system. The present study utilized an intraventricular injection of adeno-associated virus (AAV) to effectively block the PERK pathway in astrocytes. Moreover, MANF-siRNA was employed to suppress endogenous MANF expression, while rhMANF was used as an exogenous supplement. 2,3,5-Triphenyltetrazolium chloride (TTC), modified neurological severity score (mNSS), adhesive removal test, Golgi staining, hematoxylin-eosin (HE) staining, western blot, and enzyme-linked immunosorbent assay (ELISA) were applied to evaluate the protective effects of PERK pathway and the expression of MANF in astrocytes. In vitro experiments, ELISA, cell counting kit-8 (CCK-8), and western blot were used to detect the mechanisms by which MANF regulates neuroinflammation. The results showed that blocking the astrocytic PERK pathway decreased MANF expression, aggravated synaptic loss, and exacerbated infarct volume and neurological outcomes. Conversely, cellular experiments showed that activation of PERK increased MANF expression, promoted synaptic protein expression, and increased neuronal cell viability. Additionally, increasing exogenous MANF inhibited STAT3 phosphorylation, reduced the release of inflammatory factors, and improved neuronal cell viability. In conclusion, our study demonstrates that after stroke, astrocytes activate PERK and upregulate MANF expression, which inhibits STAT3 phosphorylation, reduces proinflammatory cytokine release, rescues neuronal synapse loss, and promotes the recovery of neurological function in mice.

Keywords:  MANF; PERK; STAT3; astrocyte; inflammation; stroke; synaptic remodeling

DOI:  https://doi.org/10.1155/np/6776608
Cancers (Basel). 2025 Aug 22. pii: 2731. [Epub ahead of print]17(17):

Targeting Cancer Translational Plasticity: IRES-Driven Metabolism and Survival Within the Tumor Microenvironment.

Fabrizio Damiano, Benedetta Di Chiara Stanca, Laura Giannotti, Eleonora Stanca, Angela Francesca Dinoi, Luisa Siculella.

  The tumor microenvironment creates strong stress conditions, including hypoxia and nutrient depletion, which cause the blocking of cap-dependent translation. Under stressful conditions, cancer cells exploit the cap-independent translation mechanism mediated by internal ribosome entry site (IRES), which ensures continued protein synthesis. IRES elements located in the 5' untranslated regions of specific mRNAs allow selective translation of key anti-apoptotic and adaptive proteins. These proteins promote cellular processes that sustain cell survival, among them metabolic reprogramming, redox balance, and epithelial-to-mesenchymal transition, thus facilitating tumor progression and therapy resistance. IRES activity is dynamically regulated by IRES trans-acting factors, such as YB-1, PTB, and hnRNPA1, which respond to cellular stress by enhancing translation of crucial mRNAs. Emerging therapeutic strategies include pharmacological IRES inhibitors, RNA-based approaches targeting ITAF interactions, and IRES-containing vectors for controlled therapeutic gene expression. A deeper understanding of translational reprogramming, IRES structural diversity, and ITAF function is essential to develop targeted interventions to overcome therapeutic resistance and eliminate persistent tumor cell populations.

Keywords:  IRES-mediated translation; Warburg effect; angiogenesis; apoptosis resistance; cellular plasticity; hypoxia; metabolic reprogramming

DOI:  https://doi.org/10.3390/cancers17172731
Cell Rep Med. 2025 Sep 08. pii: S2666-3791(25)00395-7. [Epub ahead of print] 102322

Modulation of fibronectin extracellular matrix enhances anti-tumor efficacy of immune checkpoint blockade.

Kabir A Khan, Maresa Caunt Mitzner, William Cruz-Munoz, Grant Li, Patricia Himmels, Ping Xu, Hung Yang Kuo, Raj Jesudason, Alvin Gogineni, Robby Weimer, Annabelle Chow, Robert Piskol, Iacovos P Michael, Weilan Ye, Robert S Kerbel.

  The success of immune checkpoint inhibitors is limited by multiple factors, including poor T cell infiltration and function within tumors, partly due to a dense extracellular matrix (ECM). Here, we investigate modulating the ECM by targeting integrin α5β1, a major fibronectin-binding and organizing integrin, to improve immunotherapy outcomes. Use of a function-blocking murinized α5β1 antibody reduces fibronectin fibril formation, enhances CD8+ T cell transendothelial migration, increases vascular permeability, and decreases vessel-associated collagen. These changes culminate in improving the effectiveness of PD-L1 blockade, alone or with chemotherapy, in the E0771 breast cancer model. Clinically, high integrin alpha 5 (ITGA5) expression correlates with worse survival in patients treated with atezolizumab as monotherapy or combined with chemotherapy or anti-angiogenic therapies in numerous clinical trials. Overall, our studies suggest that ECM-modulating approaches could be used as a future strategy to increase the proportion of patients who respond to immune checkpoint inhibition and other immunotherapies.

Keywords:  atezolizumab; cancer; combination; extracellular matrix; fibronectin; integrin a5b1; tumor immunotherapy

DOI:  https://doi.org/10.1016/j.xcrm.2025.102322
NAR Cancer. 2025 Sep;7(3): zcaf021

Inherent single-cell heterogeneity of the transcriptional response to hypoxia in cancer cells.

Małgorzata Wilk, Thomas Knöpfel, Stana M Burger, Stellor Nlandu Khodo, Roland H Wenger.

Hypoxia-inducible factor (HIF) is a master regulator of cancer cell adaptation to tumor hypoxia and is involved in cancer progression. Single-cell (sc) differences in the HIF response allow for tumor evolution and cause therapy resistance. These sc-differences are usually ascribed to tumor microenvironmental differences and/or clonal (epi)genetic variability. However, the sc-heterogeneity of the HIF response in otherwise identical cells cultured under defined in vitro conditions has not yet been addressed. Therefore, we analyzed the sc-response to hypoxia in nonclonal cell lines and multiple clonal derivatives, including HIF-1α or HIF-2α knockouts. While HIF-1α and HIF-1 target mRNA sc-heterogeneity was slightly higher than global transcription or specific housekeeping messenger RNAs (mRNAs), HIF-2α and especially HIF-2 target mRNA sc-heterogeneity was extraordinary, and remained in independent clones following HIFα knockouts. Unexpectedly, neither HIF-2α mRNA nor nuclear protein levels correlated with target mRNA levels. Unsupervised but not supervised HIF target gene dimensionality reduction revealed the initial sample composition after scRNA-seq, demonstrating that, owing to sc-heterogeneity, individual HIF target genes are not sufficient to unequivocally identify hypoxic cancer cells. In conclusion, the pronounced intrinsic sc-heterogeneity of the HIF response represents a hitherto unrecognized feature of cancer cells that impairs clinical HIF pathway-dependent cancer cell identification and targeting.

DOI: https://doi.org/10.1093/narcan/zcaf021
Trends Endocrinol Metab. 2025 Sep 06. pii: S1043-2760(25)00177-8. [Epub ahead of print]

Contribution of metabolism-independent glucose sensing to metabolic homeostasis.

Nadia Rashid, Kavaljit H Chhabra.

  Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independent of their roles in transporting glucose. Moreover, we review the emerging roles of G protein-coupled receptors (GPCRs) in sensing glucose and, consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlights the therapeutic potential of targeting the downstream glucose signaling pathways for more efficient treatment of diabetes, obesity, and their complications.

Keywords:  G protein-coupled receptors; glucose metabolism; glucose sensing; glucose transporters; sodium-glucose co-transporters

DOI:  https://doi.org/10.1016/j.tem.2025.08.008
Cell Rep. 2025 Sep 10. pii: S2211-1247(25)01020-4. [Epub ahead of print]44(9): 116249

The hexosamine biosynthetic pathway drives tumor immune evasion via translational control of PD-L1 at the elongation level.

Bo Liu, Yingying Wu, Anyi Xiang, Yiyi Yu, Shushu Song, Ying Zhang, Jianxin Gu, Haojie Lu, Ping Xu, Fenglin Liu, Yuanyuan Ruan.

  Cancer cells reprogram cellular energetics to drive tumorigenesis and escape immunosurveillance. Nevertheless, how this is molecularly connected remains largely undefined. The hexosamine biosynthetic pathway (HBP) serves as a critical metabolic node in cancer cells that provides the basis for protein glycosylation. Herein, we show that HBP flux inhibition by knocking out its rate-limiting enzyme GFAT1 suppressed tumor growth and stimulated cytotoxic CD8+ T lymphocyte infiltration in a colorectal cancer model. GFAT1 induced the expression of the immune checkpoint PD-L1 at the translational level by bypassing signal peptide-mediated translation elongation arrest. Proteomic and glycoproteomic screening indicated that GFAT1 facilitated the N-linked glycosylation and protein expression of integrin α2/α3 subunits, leading to FAK activation and elongation factor eEF1A2 upregulation. Pharmacological inhibition of HBP noticeably enhanced the efficacy of immune checkpoint blockade in vivo. Together, these findings unravel how immune checkpoint proteins are manipulated by metabolic dysregulation, which can be exploited as metabolic vulnerability for improving immunotherapies.

Keywords:  CP: Cancer; PD-L1; glycosylation; hexosamine biosynthetic pathway; immune evasion; protein synthesis

DOI:  https://doi.org/10.1016/j.celrep.2025.116249
Am J Physiol Lung Cell Mol Physiol. 2025 Sep 08.

TGFβ induces excessive pulmonary IL-6 secretion in cystic fibrosis via PI3K.

Grace Scharf, Cynthia R Davidson, Vladimir Ustiyan, Lauren G Falkenberg, Amulya Adavalli, Jessica Meeker, Hunter Morgan, Alicia J Ostmann, Kristin M Hudock, John J Brewington, John P Clancy, Elizabeth L Kramer.

  Cystic Fibrosis (CF) is characterized by impaired mucociliary clearance and pulmonary infections. Accumulating evidence suggests that fundamentally abnormal inflammatory responses also contribute to CF pathology. TGFβ, a pleiotropic cytokine, is a modifier of CF lung disease; its mechanism of action in CF is unclear. Previous studies have shown that TGFβ induces IL-6 secretion from lung epithelium, which may drive worse pulmonary outcomes in CF and other lung diseases. However, the nature of the TGFβ/IL-6 relationship in CF is not fully understood. In this study, we demonstrated that TGFβ and IL-6 concentration were positively associated in bronchoalveolar lavage fluid from children with CF. Furthermore, pulmonary TGFβ exposure in a CF mouse model induced heightened IL-6 secretion when compared with non-CF mice. CF airway epithelial cells had increased IL-6 secretion and PI3K signaling after TGFβ exposure. In wild type airway epithelium, TGFβ exposure and CFTR inhibition synergistically provoked IL-6 secretion. Restoration of CFTR function by a CFTR modulator and inhibition of PI3K signaling both normalized IL-6 secretion from CF airway epithelial cells. These data indicate that TGFβ drives abnormal IL-6 secretion via the PI3K pathway in the CF airway, demonstrating an inherent inflammatory abnormality in CF and suggesting potential therapeutic targets.

Keywords:  IL-6; TGFbeta; airway epithelium; cystic fibrosis

DOI:  https://doi.org/10.1152/ajplung.00183.2025