bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–11–23
eleven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. The canonical ER stress IRE1α/XBP1 pathway mediates skeletal muscle wasting during pancreatic cancer cachexia.
  2. RAF inhibitors activate the integrated stress response by direct activation of GCN2.
  3. Stem cell factor regulates endothelial HIF-2α expression during hypoxia-driven pathological angiogenesis.
  4. Myokine IL-6 activity enhances post-exercise fatty acid accumulation in skeletal muscle but does not affect glycogen resynthesis.
  5. NLRP3 inhibition by VTX3232 tempers inflammation resulting in reduced body weight, hyperglycemia, and hepatic steatosis in obese male mice.
  6. Adipocytes enhance tongue cancer progression potentially via IL-6 and extracellular vesicles.
  7. Druggable genome CRISPR screening identifies the KEAP1/NRF2 axis as a mediator of PD-L1 expression.
  8. Endothelial cells as targets of immune checkpoint blockade.
  9. Cancer cell-derived IL-1β reverses chemo-immunotherapy resistance in non-small cell lung cancer.
  10. Immune suppression in MTAP-deficient cancers via glutamate metabolism and CXCL10 downregulation.
  11. Development and Preclinical Evaluation of a Zirconium-89-Labeled Immunoconjugate for Positron Emission Tomography Imaging of Leukemia Inhibitory Factor in Glioblastoma.
  1. EMBO Mol Med. 2025 Nov 17.
    The canonical ER stress IRE1α/XBP1 pathway mediates skeletal muscle wasting during pancreatic cancer cachexia.
    Aniket S Joshi, Meiricris Tomaz da Silva, Anh Tuan Vuong, Bowen Xu, Ravi K Singh, Ashok Kumar.
      Cancer cachexia is a debilitating syndrome characterized by the progressive loss of skeletal muscle mass with or without fat loss. Recent studies have implicated dysregulation of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways in skeletal muscle under various conditions, including cancer. In this study, we demonstrate that the IRE1α/XBP1 branch of the UPR promotes activation of the ubiquitin-proteasome system, autophagy, JAK-STAT3 signaling, and fatty acid metabolism in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Moreover, we show that the IRE1α/XBP1 pathway is a key contributor to muscle wasting. Skeletal muscle-specific deletion of the XBP1 transcription factor significantly attenuates tumor-induced muscle atrophy. Mechanistically, transcriptionally active XBP1 binds to the promoter regions of genes such as Map1lc3b, Fbxo32, and Il6, which encode proteins known to drive muscle proteolysis. Pharmacological inhibition of IRE1α using 4µ8C in KPC tumor-bearing mice attenuates cachexia-associated molecular changes and improves muscle mass and strength. Collectively, our findings suggest that targeting IRE1α/XBP1 pathway may offer a therapeutic strategy to counteract muscle wasting during pancreatic cancer-induced cachexia.
    Keywords:  ER Stress; Fatty Acid Oxidation; JAK-STAT; Muscle Wasting; Unfolded Protein Response
    DOI:  https://doi.org/10.1038/s44321-025-00337-w
  2. Nat Commun. 2025 Nov 17. 16(1): 10033
    RAF inhibitors activate the integrated stress response by direct activation of GCN2.
    Rebecca Gilley, Andrew M Kidger, Graham Neill, Eve Morrison, Paul Severson, Dominic P Byrne, Niall S Kenneth, Gideon Bollag, Chao Zhang, Taiana Maia de Oliveira, Patrick A Eyers, Richard Bayliss, Glenn R Masson, Simon J Cook.
      Paradoxical activation of wild type RAF by chemical RAF inhibitors (RAFi) is a well-understood 'on-target' biological and clinical response. In this study, we show that a range of RAFi drive ERK1/2-independent activation of the Unfolded Protein Response (UPR), including expression of ATF4 and CHOP, that requires the translation initiation factor eIF2α. RAFi-induced ATF4 and CHOP expression was not reversed by inhibition of PERK, a known upstream activator of the eIF2α-dependent Integrated Stress Response (ISR). Rather, RAFi exposure activated GCN2, an alternate eIF2α kinase, leading to eIF2α-dependent (and ERK1/2-independent) ATF4 and CHOP expression. The GCN2 kinase inhibitor A-92, GCN2 RNAi, GCN2 knock-out or ISRIB (an eIF2α antagonist) all reversed RAFi-induced expression of ATF4 and CHOP indicating that RAFi require GCN2 to activate the ISR. RAFi also activated full-length recombinant GCN2 in vitro and in cells, generating a characteristic 'bell-shaped' concentration-response curve, reminiscent of RAFi-driven paradoxical activation of WT RAF dimers. Activation of the ISR by RAFi was abolished by a GCN2 kinase dead mutation. A M802A GCN2 gatekeeper mutant was activated at lower RAFi concentrations, demonstrating that RAFi bind directly to the GCN2 kinase domain; this is supported by mechanistic structural models of RAFi interaction with GCN2. Since the ISR is a critical pathway for determining cell survival or death, our observations may be relevant to the clinical use of RAFi, where paradoxical GCN2 activation is a previously unappreciated off-target effect that may modulate tumour cell responses.
    DOI:  https://doi.org/10.1038/s41467-025-65376-w
  3. BMB Rep. 2025 Nov 20. pii: 6429. [Epub ahead of print]
    Stem cell factor regulates endothelial HIF-2α expression during hypoxia-driven pathological angiogenesis.
    Hayoung Jeong, Yang Hee Choi, Yubin Hwang, Minju Kim, June Hyeok Lee, Koung Li Kim, Wonhee Suh.
      Hypoxia-inducible factors (HIFs) act as master regulators of hypoxia-induced pathological angiogenesis, a hallmark of various ischemic ocular diseases. Recent evidence highlights the pivotal role of HIF-2α among HIF isoforms in endothelial cells (ECs) undergoing pathological angiogenesis under hypoxic conditions. However, the regulatory mechanisms underlying endothelial HIF-2α expression during hypoxia remain incompletely understood. Here, we demonstrated that stem cell factor (SCF) and its receptor, cKIT, upregulate HIF-2α expression in hypoxic ECs. Using the oxygen-induced retinopathy (OIR) mouse model, we observed that HIF-2α was highly expressed in cKIT-positive pathological neovessels in the retina, and SCF was upregulated mainly at astrocytes in the inner retinal layer. Experiments using cKIT mutant mice and anti-SCF neutralizing antibody demonstrated that inhibition of SCF/cKIT signaling significantly reduced retinal HIF-2α expression and pathological angiogenesis in mice with OIR. Moreover, HIF-2α inhibition abolished the SCF-induced increase in the angiogenic activity of human umbilical vein ECs (HUVECs) under hypoxic conditions. Mechanistic studies in HUVECs revealed that SCF enhanced HIF-2α protein levels without affecting its mRNA levels, through AKT- and ERK1/2-dependent phosphorylation of ribosomal protein S6 kinase β-1 under hypoxia. These findings provide novel insights into the regulatory mechanisms controlling HIF-2α expression in angiogenic ECs during hypoxia and suggest that the SCF/cKIT/HIF-2 axis in hypoxic ECs represents a crucial pathway in the regulation of pathological angiogenesis in ischemic ocular diseases.
  4. Mol Metab. 2025 Nov 14. pii: S2212-8778(25)00190-5. [Epub ahead of print] 102283
    Myokine IL-6 activity enhances post-exercise fatty acid accumulation in skeletal muscle but does not affect glycogen resynthesis.
    Timothy M Kistner, Beckey Trinh, Karl Mfeketo, Gerrit Van-Hall, Bente K Pedersen, Daniel E Lieberman, Helga Ellingsgaard.
      During exercise, myokine interleukin 6 (IL-6) plays a variety of metabolic roles including acting as a muscular energy sensor and liberating somatic energy stores. While the effects of IL-6 are relatively well-defined during exercise, its role in muscular metabolism during exercise recovery in humans has not been addressed. To test whether myokine IL-6 allocates fat and glucose towards muscle, we conducted a randomized double-blind trial with 30 men (Age: 25.2 ± 3 yrs. BMI: 23.0 ± 1.5 kg/m2) where participants exercised at a moderate intensity for two hours and received either tocilizumab to block IL-6 activity, or placebo. Continuous infusions of isotopically labeled palmitate, glucose, and glycerol paired with blood, breath, and muscle samples were used to measure muscle-specific metabolism. IL-6 blockade did not affect exercise performance, substrate utilization, or glucose, fatty acid and glycerol kinetics during exercise. During recovery, IL-6 blockade decreased the appearance of oral glucose and lowered the insulin response to a glucose drink. Despite this difference in glucose and insulin, the rate of post-exercise glycogen resynthesis before and after the ingestion of glucose was not altered between groups. Although IL-6 blockade did not affect lipolysis during exercise, it attenuated the accumulation of esterified oleate in muscle during recovery before the glucose drink was given. Furthermore, IL-6 blockade attenuated IL-1RA production in recovery but did not alter IL-10 secretion. Together, these results imply that during recovery from moderate-intensity exercise, myokine IL-6 primarily regulates fatty acid metabolism within muscle and leaves glucose metabolism largely unaffected. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT05349149).
    Keywords:  energy metabolism; exercise; interleukin-6; lipid metabolism; myokines; recovery; tocilizumab
    DOI:  https://doi.org/10.1016/j.molmet.2025.102283
  5. Mol Metab. 2025 Nov 14. pii: S2212-8778(25)00189-9. [Epub ahead of print] 102282
    NLRP3 inhibition by VTX3232 tempers inflammation resulting in reduced body weight, hyperglycemia, and hepatic steatosis in obese male mice.
    Jennyfer Bultinck, Shendong Yuan, Ludovico Cantuti-Castelvetri, Lander Brosens, Debby Bracke, James Collins, Jens Goethals, Christina Christianson, John Nuss, Kathleen Ogilvie.
      The NLRP3 inflammasome is a key innate immune sensor that orchestrates inflammatory responses to diverse stress signals, including metabolic danger cues. Dysregulated NLRP3 activation has been implicated in chronic diseases such as type 2 diabetes, atherosclerosis, and neurodegeneration, underscoring the broad pathophysiological role of the NLRP3 pathway. In the context of obesity and its associated conditions, NLRP3 inhibition by VTX3232, an oral, selective, and brain-penetrant NLRP3 inhibitor, potently suppressed the release of proinflammatory cytokines (IL-1β, IL-18, IL-1α, IL-6, and TNF) from macrophages and microglia stimulated with metabolic stressors including palmitic acid and cholesterol crystals. Moreover, NLRP3 inhibition by VTX3232 also blocked NLRP3-driven insulin resistance in primary human hepatocytes and adipocytes while normalizing the acute phase response and FGF-21 secretion in hepatocytes under palmitic acid-induced inflammation. In vivo, NLRP3 inhibition by VTX3232 reduced systemic and tissue-specific inflammation in a mouse model of diet-induced obesity, reflected by decreased circulating inflammatory mediators, reduced hepatic inflammation, fewer crown-like structures in adipose tissue, and diminished hypothalamic gliosis. These anti-inflammatory effects were accompanied by improvements in body weight, food intake, and obesity-associated comorbidities such as hyperglycemia, hepatic steatosis, and markers of cardiovascular and renal disease. Notably, these effects were confined to the context of obesity, as no impact was observed in lean mice. When combined with glucagon-like peptide-1 receptor agonism by semaglutide, NLRP3 inhibition by VTX3232 yielded additive metabolic benefits, highlighting complementary mechanisms of action. Together, these findings reinforce the biological rationale for targeting NLRP3 in inflammatory conditions such as obesity, expand on the role of NLRP3 in metabolic inflammation, and underscore the importance of continued investigation into the NLRP3 pathway as a central node in cardiometabolic disease.
    Keywords:  Drug Therapy; Inflammation; Insulin Resistance; Metabolism; Obesity; Steatosis
    DOI:  https://doi.org/10.1016/j.molmet.2025.102282
  6. Sci Rep. 2025 Nov 21. 15(1): 41191
    Adipocytes enhance tongue cancer progression potentially via IL-6 and extracellular vesicles.
    Johanna Peltonen, Riia Tiikkaja, Laura Ketomäki, Sane Taivaanlahti, Tiina Kaakkuriniemi, Susanna Kokkonen, Janne Heikkinen, Sanna Palosaari, Janne Väisänen, Jukka Tikanto, Petri Koivunen, Ahmed Al-Samadi, Maija Risteli, Tuula Salo, Pirjo Åström, Krista Juurikka.
      Obesity is associated with the increased incidence of various cancers. However, the connection between high body mass index and oral cancer risk is partly controversial, and the mechanistic role of adipocytes is largely unknown. We aimed to study the prognostic value and function of adipose tissue in oral tongue squamous cell carcinoma (OTSCC). The amount of adipocytes in OTSCC samples correlated positively with tumour size. High tumoural inflammatory cell count predicted better overall survival. Patient-derived adipose tissue and adipocytes (differentiated from adipose tissue-derived mesenchymal stem cells) induced the proliferation of OTSCC cells in vitro. Moreover, adipocytes increased the migration of cancer cells from both primary and metastatic sites without the need for direct cell-cell contact. Various cytokines, including interleukin 6 (IL-6), were present at high levels in adipocyte-OTSCC co-cultures, and inhibition of IL-6 signalling markedly reduced cancer cell migration. Moreover, the adipocyte-derived extracellular vesicles (EVs) induced OTSCC cell invasion. We conclude that adipocytes increase the proliferation of cancer cells and enhance their motility without direct cell contact. The protumourigenic effect of adipocytes is likely mediated by secreted cytokines, such as IL-6, and transported via EVs.
    Keywords:  Adipocytes; Extracellular vesicles; Interleukin-6; Oral tongue cancer
    DOI:  https://doi.org/10.1038/s41598-025-24711-3
  7. Commun Biol. 2025 Nov 19. 8(1): 1610
    Druggable genome CRISPR screening identifies the KEAP1/NRF2 axis as a mediator of PD-L1 expression.
    Fidan Seker-Polat, Magdalena Rogozinska, Youngho Ban, Fatih Abdula, Kadir Buyukcelebi, Ping Xie, Jie Fan, Neda Abbaszadeh, Yasemin Kingham, Seyedeh Zahra Paylakhi, Bin Zhang, Mazhar Adli.
      Cancer cells rapidly induce PD-L1 expression in response to inflammatory cytokines such as IFNγ from cytotoxic T cells. Increased surface PD-L1 is a primary mechanism of cancer cells evading cytotoxic T-cell-mediated immune clearance. Identifying how cancer cells increase PD-L1 expression may yield clinically relevant immune checkpoint regulators. However, the key regulators and molecular mechanisms mediating rapid PD-L1 induction are yet to be understood entirely. To identify targetable mechanisms controlling cytokine-induced PD-L1 expression, we performed functional CRISPR gene KO screening with a custom-designed sgRNA library that targets "druggable" genes. We performed the screening in 6 different cancer lines: 3 ovarian (OVCAR4, CaOV3, and SKOV3) and three pancreatic cancer (MiaPaca2, ASPC1 and KP4) cell lines. The screening recovered the known regulators of PD-L1 expression and uncovered several novel regulators of PD-L1 that control its expression in all cell lines or in a cancer-type-specific fashion. For example, while genetic or pharmacological depletion of CSNK1A1 results in reduced PD-L1 expression in ovarian cancer cells, CDK1 depletion modulates PD-L1 in pancreatic cancer cell lines. Significantly, we discovered that KEAP1 depletion or pharmacological inhibition diminishes PD-L1 in all cell lines tested (n = 6). Mechanistically, KEAP1 depletion-mediated reduced PD-L1 is due to transcriptional repression of the PD-L1 gene by NRF2 activation. As such, depletion of NRF2 restores PD-L1 expression, while its overexpression leads to diminished PD-L1 expression. Supporting this, pharmacological NRF2 activation resulted in significant antitumor immunity with increased cytotoxic effector T cell infiltration and reduced exhausted T cells, resulting in smaller xenografted tumors. These findings establish the KEAP1/NRF2 axis as a novel and potentially druggable mechanism of IFNγ-meditated PD-L1 expression in cancer cells.
    DOI:  https://doi.org/10.1038/s42003-025-08983-z
  8. J Immunother Cancer. 2025 Nov 16. pii: e013144. [Epub ahead of print]13(11):
    Endothelial cells as targets of immune checkpoint blockade.
    Alan J Korman, Matthew Taylor, F Stephen Hodi.
      The tumor vasculature acts as the gatekeeper to the tumor microenvironment, thus regulating the ability of immune cells to roll, anchor, and cross the endothelium from blood to tissue. While the role of endothelial cells (EC) in T Cell migration and extravasation has been extensively studied, the ability of ECs to control T Cell function is less well appreciated. Several well-characterized regulators of T Cell function are expressed by ECs, while others are induced by soluble factors required for EC development and differentiation. Targeting the molecules expressed by immunomodulatory ECs may provide approaches to improve tumor immunotherapy.
    Keywords:  Immune Checkpoint Inhibitor; Immune modulatory
    DOI:  https://doi.org/10.1136/jitc-2025-013144
  9. Nat Commun. 2025 Nov 21. 16(1): 10244
    Cancer cell-derived IL-1β reverses chemo-immunotherapy resistance in non-small cell lung cancer.
    Anaïs Perrichet, Julie Lecuelle, Emeric Limagne, Marie Thiefin, Hélène Bellio, Pierre Jacob, Romain Aucagne, Aziza Aznague, Pauline Russo, Flavie Gaucher, Nicolas Roussot, Xingping Yang, Thibault Vernet, Lisa Nuttin, Alis Ilie, David Rageot, Valentin Derangère, Titouan Huppe, Alfred Zippelius, Bertrand Routy, Caroline Truntzer, Fanny Chalmin, François Ghiringhelli, Cédric Rébé.
      Many non-small cell lung cancer (NSCLC) patients remain unresponsive to the current standard of care, which includes chemotherapy and immune checkpoint inhibitors, like anti-PD-1/PD-L1 antibodies. While interleukin (IL)-1β is known to promote lung cancer growth in humans and mice, we show here that IL-1β administration or overexpression overcomes resistance to classical chemo-immunotherapy (cisplatin/pemetrexed/anti-PD-1) in mouse lung cancer models. The antitumor effects of IL-1β rely on cancer cell-derived CXCL10 which mediates CD8 T cell recruitment at the tumor site. In lung cancer cells, Thioredoxin Interacting Protein (TXNIP) induces mitochondrial DNA (mtDNA) release in the cytosol, activating Absence in Melanoma 2 (AIM2) inflammasome, which subsequently triggers IL-1β and CXCL10 secretion, thereby reversing chemo-immunotherapy resistance. The clinical relevance of our findings is supported by the transcriptomic analysis of patient tumors, showing that high expression of IL1B, IL1R1, AIM2 and/or TXNIP is associated with better response to immunotherapy in NSCLC patients. Additionally, drug screening identifies MEK and MDM2 inhibitors as inducers of TXNIP expression capable of reversing resistance to chemo-immunotherapy. This study highlights a positive role of IL-1β in lung cancer treatment and suggests that enhancing IL-1β production at the tumor site can overcome resistance to chemo-immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-025-64839-4
  10. Front Immunol. 2025 ;16 1634342
    Immune suppression in MTAP-deficient cancers via glutamate metabolism and CXCL10 downregulation.
    Wen-Hsin Chang, Jun Zhang, Qi-Sheng Hong, Ching-Hsien Chen.
       Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; however, their efficacy remains limited in certain tumor subtypes, including those deficient in methylthioadenosine phosphorylase (MTAP). MTAP-deficient cancers are characterized by immunosuppressive tumor microenvironments (TMEs) and poor T cell infiltration, as suggested by large-scale transcriptomic analyses. Yet, the underlying mechanisms and therapeutic vulnerabilities remain poorly defined.
    Methods: We employed murine tumor models and transcriptomic profiling to investigate the immunosuppressive features of MTAP-deficient tumors. To identify actionable vulnerabilities, we conducted a high-throughput screen using the LOPAC1280 compound library. Functional assays were performed to evaluate the effects of candidate compounds on tumor growth and immune signaling.
    Results: MTAP-deficient tumors exhibited significantly reduced CD45+ immune cell infiltration and resistance to ICI therapy. Transcriptomic analyses revealed that MTAP-deficient cancer cells reprogram immune signaling pathways and suppress the expression of CXCL10, a key chemokine for T cell recruitment, thereby contributing to a non-inflamed, "cold" TME. High-throughput screening revealed an increased dependence on glutamate metabolism in MTAP-deficient cells. Several glutamate pathway inhibitors, including the clinically tested glutaminase inhibitor CB-839, selectively impaired their growth. Remarkably, CB-839 also restored CXCL10 expression, particularly under immune co-culture conditions, indicating a dual effect of direct cytotoxicity and immune activation.
    Conclusion: These findings uncover a novel link between glutamate metabolism and immune modulation in MTAP-deficient tumors. Our study provides mechanistic and preclinical support for targeting glutamate pathways to both suppress tumor growth and convert immune-cold tumors into more immunoresponsive states, offering a promising strategy to enhance ICI efficacy in this challenging cancer subtype.
    Keywords:  CXCL10; MTAP deficiency; glutamate metabolism; immunosuppression; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1634342
  11. ACS Pharmacol Transl Sci. 2025 Nov 14. 8(11): 3886-3895
    Development and Preclinical Evaluation of a Zirconium-89-Labeled Immunoconjugate for Positron Emission Tomography Imaging of Leukemia Inhibitory Factor in Glioblastoma.
    Emily Betancourt Fernández, Julia Baguña Torres, Raffaella Iurlaro, Isabel Cuartas, Martha Sahylí Ortega Pijeira, Sofía Rodríguez Fernández, Sergi Velasco-Vila, Joan Seoane, J Raul Herance.
      Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine secreted by tumor cells to evade immune detection, contributing to tumor progression and resistance to therapy. Targeting LIF has emerged as a promising strategy, with anti-LIF therapies in clinical trials across a variety of cancers. Glioblastoma, a highly aggressive LIF-secreting brain tumor, is a critical target for these emerging therapies. This study aimed to develop an anti-LIF immunoPET agent for monitoring LIF expression in vivo, improving detection and targeted treatment strategies for glioblastoma. An anti-LIF antibody was conjugated to p-SCN-Bz-DFO and radiolabeled with positron-emitting zirconium-89 (89Zr). Target binding properties and stability of the radioimmunoconjugate were assessed by ELISA and size exclusion chromatography. The biodistribution of [89Zr]-Zr-DFO-anti-LIF was evaluated by PET/CT imaging in an orthotopic glioblastoma mouse model with LIF-positive (GL261N) and LIF-negative (GL261N-CRISPR/LIF) tumors at 24, 48, and 72 hours post-administration. Tumor LIF levels were measured ex vivo by immunohistochemistry. Mass spectrometry determined 2.4 ± 0.3 chelators per antibody molecule. Competitive ELISA demonstrated unaltered affinity post-conjugation. Radiolabeling at a 1 MBq of 89Zr per 5 μg of anti-LIF ratio achieved >68% yield, >95% purity, and 0.17 ± 0.03 MBq/μg specific activity. The radioimmunoconjugate remained >90% intact after 72 h in both saline and mouse serum. PET imaging revealed specific accumulation in LIF-positive brain tumors in vivo (6 ± 1.26 % ID/mL at 72 h), which was 2-fold higher than that observed in the GL261N-CRISPR/LIF model. [89Zr]-Zr-DFO-anti-LIF was successfully synthesized, exhibiting specificity and stability in vitro and in vivo, thus supporting its potential for glioblastoma monitoring, as well as guiding anti-LIF therapies.
    Keywords:  cancer immunotherapy; glioblastoma; leukemia inhibitory factor; positron emission tomography; zirconium-89
    DOI:  https://doi.org/10.1021/acsptsci.5c00093
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