bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2026–05–03
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Metabolic and transcriptional plasticity supports CD8+ T cell resilience and anti-tumor immunity under nutrient stress.
  2. Hypoxia-Induced Fibroblast IL-6 Promotes Immunosuppressive Macrophage Phenotypes in Pancreatic Cancer.
  3. Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly.
  4. Sarcopenia promotes tumorigenesis by disrupting NOTCH-SDC2-regulated biogenesis of muscle-derived extracellular vesicles.
  5. Tumor-derived complement C3 overexpression in STK11-mutant lung adenocarcinoma drives tumor growth and immune checkpoint inhibitor resistance.
  6. The atypical E3 ligase HOIL-1 safeguards the ribosome during cellular stress.
  7. NAD-dependent redox control enables endothelial quiescence and vascular stabilization during angiogenesis.
  8. Targeting serine metabolism boosts antimycobacterial immunity during Mycobacterium tuberculosis H37Rv Infection.
  9. Palmitic acid reprograms neutrophils to compromise vascular integrity and promote breast cancer lung metastasis.
  10. Sphingosine-1-Phosphate Promotes FOS Activation in Osteosarcoma Under Tumor Acidosis.
  1. Immunity. 2026 Apr 29. pii: S1074-7613(26)00144-5. [Epub ahead of print]
    Metabolic and transcriptional plasticity supports CD8+ T cell resilience and anti-tumor immunity under nutrient stress.
    Michael Scaglione, Montana Knight, Krittin Trihemasava, Kelly Rome, Anne-Sophie Archambault, Juhee Oh, Erin Tanaka, Elise Hall, Tran Ngoc Van Le, Caleb L Lines, Brian Goldspiel, Hossein Fazelinia, Clemence Queriault, Lucien Turner, Tanay Parnaik, Jimmy Xu, Morgan Brown, Oishi Bardhan, Jessie Axsom, Frederick C Bennett, Lynn A Spruce, Caroline Bartman, Clementina Mesaros, Ramon I Klein Geltink, Crystal S Conn, Will Bailis.
      CD8+ T cells need to function in complex environments with varied nutrient availability, including the tumor microenvironment and inflamed tissues. The mechanisms that allow CD8+ T cells to maintain immune function in these perturbed settings are poorly understood. Here, we show that CD8+ T cells adapt to nutrient stresses over time, reconfiguring gene-regulatory and metabolic networks to license functional recovery. Under acute stress, T cells reoriented translational programming, which limited nutrient demand and prioritized stress-sensitive metabolic and transcriptional responses. Within these responses, the transcription factors activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein gamma (CEBPG) jointly established an adaptive metabolic program, promoting amino acid synthesis and uptake while maintaining mitochondrial metabolism. Despite diminished energetic capacity under environmental stress, this program sustained central carbon metabolism. This subsequently mitigated cellular dysfunction and potentiated anti-tumor immunity. Altogether, we demonstrate that biosynthetic plasticity via translational and metabolic reprioritization confers T cell resilience in unfavorable environments, offering potential strategies to enhance immunotherapies.
    Keywords:  ATF4; CD8(+) T cells; CEBPG; GCN2; HRI; T cell exhaustion; T cells; amino acids; anti-tumor immunity; immunometabolism; integrated stress response; mTOR; nutrient stress; polysome profiling; stress adaptation; translation; tumor-infiltrating lymphocyte
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.004
  2. Cells. 2026 Apr 13. pii: 683. [Epub ahead of print]15(8):
    Hypoxia-Induced Fibroblast IL-6 Promotes Immunosuppressive Macrophage Phenotypes in Pancreatic Cancer.
    Sean Hannifin, Ashley M Mello, Tenzin Ngodup, Nam Hoon Kim, Marina Pasca di Magliano, Kyoung Eun Lee.
      Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by a dense fibroinflammatory stroma and profound hypoxia. Using pancreatic stellate cell-tumor organoid coculture models and single-cell RNA sequencing analyses, we uncover that hypoxia-driven fibroblast reprogramming promotes immunosuppressive macrophage phenotypes in PDAC. Mechanistically, hypoxia acts through tumor-fibroblast crosstalk to increase IL-6 expression in fibroblasts; in turn, fibroblast-derived IL-6 induces expression of arginase 1 (ARG1), a key mediator of immunosuppression, in macrophages via activation of the JAK/STAT signaling pathway. Consistent with these findings, macrophages enriched for hypoxia signatures are strongly associated with elevated immunosuppression programs and IL6/JAK/STAT3 signaling signatures in PDAC. Our study reveals a paracrine mechanism by which hypoxia coordinates tumor cell, fibroblast, and macrophage interactions to promote immune suppression in PDAC.
    Keywords:  ARG1; IL6; JAK; fibroblast; hypoxia; macrophage; pancreatic cancer
    DOI:  https://doi.org/10.3390/cells15080683
  3. Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2518812123
    Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly.
    Miriam S Götz, Dan J Hayman, Gracie Adams, Fumiaki Obata, Mirre J P Simons.
      Stress response pathways are emerging as conserved modulators of lifespan. The prevailing hypothesis is that activation of stress-responsive pathways, including the amino acid deprivation arm of the integrated stress response (ISR; the GCN2-ATF4 pathway), is prolongevity. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in longevity in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNAi) of dATF4 extends lifespan. We confirmed that dATF4 activity was successfully modulated using a fluorescent dATF4 activation reporter. Borrelidin, a tRNA synthetase inhibitor, significantly reduced lifespan in a both dATF4 and diet-dependent manner, independent of microbial load, showing our modulation of dATF4 altered nutrient to ISR signaling. We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown may upregulate proteostasis and DNA repair pathways. Our work reveals that ATF4 may exhibit a dual, dose-, and context-dependent role in aging. Chronic dATF4 activation is detrimental in flies, while chronic suppression is prolongevity. The GCN2-ATF4 pathway thus qualifies as a modifiable control of lifespan with cross-species relevance.
    Keywords:  aging; borrelidin; integrated stress response; tRNA; transcriptomics
    DOI:  https://doi.org/10.1073/pnas.2518812123
  4. Nat Commun. 2026 Apr 27.
    Sarcopenia promotes tumorigenesis by disrupting NOTCH-SDC2-regulated biogenesis of muscle-derived extracellular vesicles.
    Kah Yong Goh, Wen Xing Lee, Qian Gou, Sze Mun Choy, Shi Chee Ong, Priya D Gopal Krishnan, Huaxin Wang, Lewin Raymarc Roldan Turqueza, Qian Hui Tan, Kenon Chua, Shang Li, Jun Nishiyama, Nathan Harmston, Hong-Wen Tang.
      Sarcopenia is an age-related condition characterized by loss of skeletal muscle mass and strength and is associated with increased cancer incidence and mortality, yet how muscle decline promotes tumorigenesis remains unclear. Here, we show that skeletal muscle functions as an anti-tumor organ by secreting extracellular vesicles (EVs) that suppress tumor growth. Using Drosophila melanogaster and mouse cancer models, we demonstrate that muscle-derived EVs inhibit tumorigenesis. In contrast, sarcopenic muscle exhibits reduced EV secretion and altered EV cargo, resulting in loss of tumor-suppressive activity. We identify miR-7a-5p as a tumor-suppressive microRNA enriched in EVs from healthy muscle but diminished with aging, where it restrains tumor growth by inhibiting TEAD1 signaling. Mechanistically, muscle EV biogenesis is regulated by a NOTCH-SDC2 pathway that declines with age but is reactivated by exercise. Together, these findings define a muscle-to-tumor communication axis with therapeutic potential.
    DOI:  https://doi.org/10.1038/s41467-026-72410-y
  5. Cancer Immunol Res. 2026 Apr 28.
    Tumor-derived complement C3 overexpression in STK11-mutant lung adenocarcinoma drives tumor growth and immune checkpoint inhibitor resistance.
    Sora Suzuki, Bojidar Kandar, Catrina Ting, Peter Deraska, Te-An Chen, Thejaswini Giridharan, Anm Nazmul H Khan, Kristopher Attwood, Han Yu, Kayla Catalfamo, Prashant K Singh, Ryan T Bushey, Elizabeth B Gottlin, Michael J Campa, Edward F Patz, Daniel Ajona, Ruben Pio, Brahm H Segal, Edwin H Yau.
      Loss-of-function STK11 mutations occur in 15-20% of lung adenocarcinomas (LUAD) and correlate with immunotherapy failure and worse survival. By integrating analysis of human tumor samples, a human LUAD cell line panel, and CCLE and TCGA datasets, we found that C3 production was increased in human STK11-mutant versus STK11-wildtype LUAD, modulated by LKB1 loss, while high C3 expression in STK11-mutant LUAD was associated with worse survival. STK11-KO in syngeneic murine LUAD tumors resulted in increased neutrophil and reduced T cell infiltration and anti-PD-1 resistance. STK11-KO tumor growth was similar in C3-/- versus wildtype mice. In contrast, C3 deletion in STK11-KO tumors resulted in dramatic inhibition of tumor growth and enhanced sensitivity to anti-PD-1 in immunocompetent mice but had no significant effect in CD8-depleted wildtype mice or in nude mice, pointing to tumor-derived C3 promoting immune evasion. Mechanistically, STK11 loss drove tumor-derived C3 production and downstream CXCL2 and complement factor H (CFH) production that promoted immune evasion and impaired anti-PD-1 efficacy. Our results show a C3-driven signaling axis for STK11-mutant LUAD promoting immune evasion and identifies therapeutic targets to render these tumors sensitive to anti-PD-1.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0534
  6. Nat Cell Biol. 2026 Apr 30.
    The atypical E3 ligase HOIL-1 safeguards the ribosome during cellular stress.
    Todd Douglas, Pengju Nie, Jiasheng Zhang, Kyrillos S Abdallah, Zhiping Wu, Meghan McReynolds, Kazuhiro Iwai, Junmin Peng, Wendy V Gilbert, Lawrence H Young, Craig M Crews.
      The ribosome has emerged as a signalling hub that can sense metabolic perturbations and coordinate responses that either restore homeostasis or initiate cell death. The range of insults that signal via the ribosome and the mechanisms governing such cell fate decisions remain uncharacterized. Here we identify the atypical E3 ligase HOIL-1 as an unexpected node in the ribosome signalling network that resolves cellular stress. We find that truncating HOIL-1 mutations associated with dilated cardiomyopathy exacerbate cardiac dysfunction in mice and broadly sensitize cells to nutrient and translational stress. These diverse signals converge on the MAP3K ZAKα, a sentinel of ribotoxic stress. Mechanistically, HOIL-1 promotes ribosome ubiquitination and facilitates cytoprotective ribosome-associated quality control. HOIL-1 loss of function causes glucose starvation to become ribotoxic, leading to ZAKα-dependent ATF4 activation and disulfidptosis driven by the cystine-glutamate antiporter xCT. These data reveal a molecular circuit controlling cell fate during nutrient stress and establish the ribosome as a signalosome that responds to cellular glucose levels.
    DOI:  https://doi.org/10.1038/s41556-026-01936-6
  7. Cell Metab. 2026 Apr 29. pii: S1550-4131(26)00142-7. [Epub ahead of print]
    NAD-dependent redox control enables endothelial quiescence and vascular stabilization during angiogenesis.
    Wencao Zhao, Wenkai Zhu, Trace Thome, Ioana Soaita, Jae Woo Jung, Michael C Noji, Jian Li, Huajun Bai, Yansen Xiao, Yifan Yang, Chelsea Thorsheim, Wei Zhou, Yijun Yang, Kristina Li, Jonathan J Edwards, Ivan A Kuznetsov, Boa Kim, Joseph A Baur, Zoltan Arany.
      Angiogenesis requires endothelial cells (ECs) to toggle between quiescence versus proliferation, migration, and invasion. While activation from quiescence is well characterized, mechanisms governing the return from proliferation to quiescence (PtoQ) remain unclear. We show here that metabolic rewiring during PtoQ renders ECs sensitive to oxidative stress, requiring nicotinamide adenine dinucleotide (NAD) turnover for protection. Limiting EC NAD does not affect proliferation or migration but prevents cell-cell contact formation and quiescence acquisition during PtoQ. In vivo and ex vivo, limiting EC NAD permits initial sprouting but impairs vascular stabilization and plexus formation. Mechanistically, NAD suppresses mitochondria-derived hydrogen peroxide (H2O2) during PtoQ. Exogenous H2O2 mimics NAD deficiency, whereas its removal rescues PtoQ. In pathological settings, inhibiting NAD synthesis limits exuberant angiogenesis of retinopathy and tumors. In summary, we unveil metabolic events critical for PtoQ, a poorly studied component of angiogenesis, and point to new ways to suppress pathological angiogenesis.
    Keywords:  H(2)O(2); NAD; NADPH; NAMPT; angiogenesis; endothelial cells; metabolism; quiescence
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.004
  8. Mol Cells. 2026 Apr 26. pii: S1016-8478(26)00057-9. [Epub ahead of print] 100366
    Targeting serine metabolism boosts antimycobacterial immunity during Mycobacterium tuberculosis H37Rv Infection.
    Sang-Hun Son, Ji-Ae Choi, Jaewhan Kim, Tam Doan Nguyen, Junghwan Lee, Doyi Son, Seoyeon Jo, Chang-Hwa Song.
      Serine metabolism is pivotal in regulating immune cell function and molding the host microenvironment during infection, yet its impact on antimycobacterial immunity remains elusive. Here, we probe the role of serine metabolism in Mycobacterium tuberculosis (Mtb)-infected macrophages. We reveal that Mtb infection induces enzymes associated with the serine synthesis pathway (SSP) and serine transporters. Moreover, inhibition of the key SSP enzyme or restriction of exogenous serine boosts antimycobacterial immunity in both in vitro and in vivo. Depletion of serine reduces reactive oxygen species (ROS) levels by diminishing the levels of reduced nicotinamide adenine dinucleotide. This ROS reduction destabilizes hypoxia-inducible factor 1 alpha, impairing glucose uptake and ATP production. Consequently, reduced ATP production activates AMP-activated protein kinase, which inhibits mTOR and induces autophagy, thereby exerting antimycobacterial effect. These findings underscore serine's role as a crucial immune metabolite during Mtb infection and propose that manipulating serine metabolism holds therapeutic promise against mycobacterial infections.
    Keywords:  AMP-activated protein kinase; Autophagy; Phosphoglycerate dehydrogenase; Reactive oxygen species; Tuberculosis
    DOI:  https://doi.org/10.1016/j.mocell.2026.100366
  9. Immunity. 2026 Apr 24. pii: S1074-7613(26)00137-8. [Epub ahead of print]
    Palmitic acid reprograms neutrophils to compromise vascular integrity and promote breast cancer lung metastasis.
    Peng Qian, Yuxin Li, Yifeng Han, Chun Xu, Peng Zou, Fuming Yang, Xiaozhen Kang, Mengdi Wu, Jie Dong, Zhengyun Zou, Jiwu Wei.
      Pre-metastatic niche formation in the lung creates a permissive microenvironment for breast cancer metastasis, characterized by metabolic reprogramming of resident cells, recruitment of suppressive neutrophils, and vascular remodeling. However, the role of lipids in regulating neutrophil-endothelial interactions, particularly in facilitating tumor cell extravasation, remains largely undefined. Here, we showed that triple-negative breast cancer established a palmitic acid-enriched lung microenvironment that drove tumor cell extravasation and colonization. Pulmonary endothelial cells were a major source of palmitic acid, which activated neutrophils to produce lipocalin-2 (LCN2) via the Toll-like receptor 4 (TLR4)-NF-κB pathway. Neutrophil-derived LCN2 disrupted endothelial tight junctions, compromised vascular integrity, and facilitated tumor cell extravasation. Targeting endothelial fatty acid synthesis using glucagon-like peptide-1 receptor agonists preserved vascular integrity and suppressed lung metastasis. These findings uncover a lipid-driven mechanism underlying metastatic organotropism and highlight metabolic intervention as a potential therapeutic strategy against breast cancer lung metastasis.
    Keywords:  breast cancer metastasis; glucagon-like peptide-1 receptor agonists; lipocalin-2; neutrophil; palmitic acid; vascular endothelial cell
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.026
  10. Acta Physiol (Oxf). 2026 Jun;242(6): e70214
    Sphingosine-1-Phosphate Promotes FOS Activation in Osteosarcoma Under Tumor Acidosis.
    Nicolò Bozzini, Margherita Cortini, Alberto Righi, Agamemnon E Grigoriadis, Michael Dack, Elizabeta Ilieva, Federica Torricelli, Veronica Manicardi, Nicola Baldini, Sofia Avnet.
       AIM: The tumor microenvironment in solid tumors is characterized by extracellular acidosis, which promotes cancer aggressiveness. In osteosarcoma, the most common primary bone cancer, a highly acidic tumor microenvironment is associated with metastasis and poor prognosis, partly due to metabolic rewiring, including changes in lipid pathways such as those involving sphingosine-1-phosphate, a bioactive sphingolipid. Sphingosine-1-phosphate has been previously implicated in histone deacetylase inhibition and gene activation. Here, we investigated whether acidosis induces nuclear sphingosine-1-phosphate accumulation via sphingosine kinase 2, leading to epigenetic activation of oncogenes like FOS in osteosarcoma.
    METHODS: Osteosarcoma spheroids were cultured under neutral or acidic conditions. Histone H3 acetylation was assessed by capillary Western blotting. FOS expression and FOS nuclear localization were analyzed. Sphingosine-1-phosphate's role was addressed through sphingosine kinase 2 silencing and inhibition (ABC294640). Functional effects were measured using colony formation assays. Patient-derived OS tissues (n = 7) were analyzed for correlations between acidity markers (LAMP2, V-ATPase), sphingosine kinase 2, and FOS expression.
    RESULTS: Acidosis increased both sphingosine kinase 2 mRNA expression after 24 h and histone H3 acetylation, which followed progressive FOS upregulation and nuclear FOS accumulation. Sphingosine kinase 2 inhibition or silencing reduced these effects and impaired clonogenicity. In patient tissues, sphingosine kinase 2 levels correlated with acidosis markers and FOS expression.
    CONCLUSIONS: We identified a novel mechanism where acidosis stimulates both nuclear sphingosine kinase 2 to synthesize sphingosine-1-phosphate and histone H3 acetylation, ultimately leading to FOS transcription. Targeting this axis decreased clonogenesis, underscoring its therapeutic potential in osteosarcoma and potentially other acid-adapted cancers.
    Keywords:  FOS; acidosis; epigenetics; osteosarcoma; sphingosine kinase 2; sphingosine‐1‐phosphate; tumor microenvironment
    DOI:  https://doi.org/10.1111/apha.70214
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