bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2026–07–12
twelve papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.
  2. Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.
  3. Lactate-induced H3K4me3 histone mark promotes PLOD1-driven prostate cancer invasion.
  4. A cold-induced GDF15-secreting adipocyte subpopulation regulates energy homeostasis through endocrine signaling.
  5. Long-term follow-up of a phase 1/2 trial of anti-GDF-15 antibody visugromab plus anti-PD-1 antibody nivolumab in anti-PD-1/-L1 relapsed/refractory solid tumors.
  6. Investigating the Role of Anti-Leukemia Inhibitory Factor Antibody on Cytokine Profile in a Mouse Model of Breast Cancer.
  7. NSUN2 integrates glucose and one‑carbon metabolism upstream of Rag GTPase-dependent mTORC1 signaling.
  8. FGF21 connects ER stress to sulfide signaling to enhance cellular resilience.
  9. The Metabolic States of Cancer-Associated Fibroblasts: Targeting Stromal Reprogramming to Impede Tumor Progression and Immune Evasion.
  10. Targeting Cystine Addiction Suppresses Breast Cancer Lung Metastasis.
  11. Plasma proteomics predicts pathological complete response and reveals LIF as a potential mediator of resistance to neoadjuvant immunochemotherapy in resectable NSCLC.
  12. CAF-derived PAI-1 serves as an EGFR ligand and fuels KRAS-mutant pancreatic cancer.
  1. Adv Sci (Weinh). 2026 Jul 07. e76202
    De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.
    Haitao Wang, Tianzhen Hua, Meiling Wang, Bingbing Meng, Yue Zhang, Chengxu Jiang, Yunhe Gao, Hongqi Yang, Jian Bo.
      Cancer-associated cachexia is a devastating syndrome characterized by progressive weight loss, reduced survival, and impaired responses to anticancer therapies. Growth differentiation factor 15 (GDF15), acting through its receptor GFRAL, has emerged as a key mediator of cachexia, yet effective and mechanistically defined strategies to neutralize this pathway remain limited. Here, we applied structure-guided de novo protein design to generate compact minibinders that selectively target the GDF15-GFRAL interaction interface. Using an integrated computational pipeline combining RFdiffusion, ProteinMPNN, and AlphaFold 3 structure prediction, we designed and experimentally validated high-affinity GDF15 minibinders with picomolar-range binding affinities and exceptional structural stability. Mutagenesis and charge-complementary rescue experiments confirm that these minibinders neutralize GDF15 through precisely engineered interface contacts. Functionally, the minibinders suppress GDF15-GFRAL signaling, inhibit downstream transcriptional responses, and robustly reverse cachexia in vivo across multiple tumor models, resulting in significant improvements in body weight and survival. Importantly, neutralization of GDF15 also restores sensitivity to anti-PD-1 immunotherapy in a GDF15-driven resistant tumor model. Combination treatment enhances CD8+ T cell infiltration and effector function within tumors, and its antitumor efficacy is strictly dependent on CD8+ T cells. Together, these findings demonstrate that de novo designed GDF15 minibinders can achieve potent, mechanism-defined neutralization of the GDF15-GFRAL axis in vivo, translating into robust physiological benefits and restoration of immunotherapy efficacy.
    Keywords:  GDF15; RFdiffusion; cancer cachexia; de novo protein design; immune checkpoint blockade
    DOI:  https://doi.org/10.1002/advs.76202
  2. Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2531623123
    Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.
    Max Schwiening, Qingyue Gao, Mark Southwood, Alexi Crosby, Stephen Moore, Jose A Valer, Niki Veale, Benjamin J Dunmore, Paul D Upton, A A Roger Thompson, Nicholas W Morrell, Stefan J Marciniak, Elaine Soon.
      Biallelic mutations in EIF2AK4, encoding Eukaryotic Translation Initiation Factor 2α kinase 4 or General Control Nonderepressible 2 (GCN2), cause pulmonary veno-occlusive disease (PVOD), a fatal form of pulmonary hypertension. The mechanisms linking GCN2 deficiency with pulmonary vascular pathology are poorly understood. To investigate this, we developed two mouse models: genetic ablation of Gcn2, to mirror GCN2-mutation positive PVOD, and a pharmacological model using mitomycin C, a drug which can cause PVOD as an idiosyncratic drug reaction. Both models were phenotyped, and lungs from wild-type and Gcn2-deficient mice were analyzed using single-cell RNA sequencing. We show that homozygous loss of Gcn2 is sufficient to induce mild pulmonary hypertension in mice. Single-cell transcriptomic profiling identified adventitial fibroblasts as the cell population exhibiting the most Gcn2-dependent transcriptional changes. Pathway analysis revealed upregulation of inflammatory signaling in Gcn2-/- adventitial fibroblasts. Consistent with this, we demonstrate a proinflammatory phenotype in Gcn2-/- mouse fibroblasts and in Gcn2-/- mice. Using a mitomycin C-induced murine model, genetic deletion of interleukin-6 (Il6) rescued the pulmonary vascular phenotype. Furthermore, chronic lipopolysaccharide exposure exaggerated pulmonary hypertension in Gcn2-/- mice, and Il6 ablation rescued both baseline and lipopolysaccharide-exacerbated disease. Pharmacological inhibition or genetic ablation of the Integrated Stress Response, which can be driven by GCN2-activation, phenocopies Gcn2 deficiency. Therefore, we establish a regulatory effect of an intact GCN2-Integrated Stress Response on IL-6 signaling. Together, we show that interleukin-6 is a critical mediator of both Gcn2 deficiency-associated and mitomycin C-triggered pulmonary vascular disease in mice and highlight IL-6-dependent pathways as potential therapeutic targets.
    Keywords:  GCN2; interleukin-6; pulmonary veno-occlusive disease
    DOI:  https://doi.org/10.1073/pnas.2531623123
  3. Cell Death Dis. 2026 Jul 07.
    Lactate-induced H3K4me3 histone mark promotes PLOD1-driven prostate cancer invasion.
    Marta Iozzo, Luigi Ippolito, Erica Pranzini, Simone Romagnoli, Giulia Gangarossa, Caterina Grillo, Sara Roccabianca, Giada Sandrini, Matteo Benelli, Giuseppina Comito, Elisa Giannoni, Paola Chiarugi.
      Prostate cancer (PCa) progression is strongly influenced by the metabolites available in the tumor microenvironment (TME), including lactic acid (LA), which is actively imported by PCa cells to boost mitochondrial metabolism and drive de novo collagen synthesis, sustaining increased malignancy. LA exploitation promotes the unbalance of tricarboxylic acid (TCA) cycle intermediates, particularly succinate and fumarate, well-known epigenetic modifiers for histone (de)methylation. Here, we show that the LA-induced increase in succinate levels affects the activating H3K4me3 methylation mark in PCa cells, promoting a pro-invasive phenotype. Notably, pharmacological targeting of H3K4me3 using OICR-9429 reduces LA-enhanced PCa cell invasiveness. Moreover, LA-induced H3K4me3 enrichment regulates the expression of procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 1 (PLOD1), a key enzyme involved in collagen maturation. Genetic impairment of PLOD1 reduces the LA-driven invasive potential of PCa cells, thereby highlighting PLOD1 as a crucial epigenetically regulated mediator of tumor invasion. Overall, our findings uncover a novel LA-fuelled metabolic-epigenetic axis that promotes the H3K4me3-mediated PLOD1 upregulation, consequently fostering PCa aggressiveness and unveiling a potential therapeutic vulnerability.
    DOI:  https://doi.org/10.1038/s41419-026-09091-4
  4. Cell Rep. 2026 Jul 04. pii: S2211-1247(26)00681-9. [Epub ahead of print]45(7): 117603
    A cold-induced GDF15-secreting adipocyte subpopulation regulates energy homeostasis through endocrine signaling.
    Chunyan Wu, Tongtong Wang, Songlin Gong, Jing Zhang, Charlotte G Mann, Min Li, Ziyu Liu, Yizhi Sun, Shenwei Shi, Zhenghong Liu, Katrien De Bock, Miroslav Balaz, John Speakman, Christian Wolfrum.
      Brown adipose tissue (BAT) regulates whole-body energy balance through uncoupling protein 1 (UCP1)-dependent thermogenesis and secretion of metabolic factors. Recent studies suggest UCP1-independent mechanisms contribute to energy balance, with UCP1 being conditionally dispensable. However, how adaptation to UCP1 deficiency is regulated remains unclear. Our single-nucleus RNA sequencing of BAT from cold-exposed Ucp1 knockout mice reveals a distinct brown adipocyte subpopulation (U2). U2 adipocytes exhibit a secretory profile enriched in batokines like growth differentiation factor 15 (GDF15), suggesting a shift toward an endocrine role. Functional analyses reveal that GDF15-GFRAL signaling is required to sustain energy expenditure in adipose tissue (AT). The Ucp1/Gfral knockout increased food intake to compensate for decreased energy expenditure in AT. Additionally, a conserved UCP1-GDF15 regulatory axis in human AT is observed. These findings identify a regulatory brown adipocyte subpopulation emerging in response to UCP1 deficiency, representing a compensatory mechanism for maintaining energy homeostasis in mammals.
    Keywords:  CP: metabolism; GDF15; GFRAL; Ucp1 knockout mice; adipose tissue; cold exposure; energy expenditure; single-nucleus RNA sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2026.117603
  5. J Hematol Oncol. 2026 Jul 09.
    Long-term follow-up of a phase 1/2 trial of anti-GDF-15 antibody visugromab plus anti-PD-1 antibody nivolumab in anti-PD-1/-L1 relapsed/refractory solid tumors.
    Ignacio Melero, María de Miguel, Elena Garralda Cabanas, Guillermo de Velasco, Markus Joerger, Juan Martín-Liberal, Maria Reig, David König, Joerg Trojan, Maria-Elisabeth Goebeler, Martin Schuler, Guzman Alonso, Reinhard Dummer, Maria E Rodríguez-Ruiz, Ramón Yarza, Giulia Pretelli, Jorge Esteban-Villarubia, Kira-Lee Koster, Paula Sabat Viltro, Marco Sanduzzi-Zamparelli, Heinz Läubli, Christine Koch, Cyrus Sayehli, Tanja Gromke, Fabricio Racca, Egle Ramelyte, Peter R Galle, Andrea Necchi, Martin Reck, Zlatko Trajanoski, Hubert Hackl, Falk Gogolla, Jaclyn Billing, Teresa Sattmann, Jörg Wischhusen, Christine Schuberth-Wagner, Julia Akdemir, Felix S Lichtenegger, Alexandra Auckenthaler, Marlene Fox, Kathrin Klar, Petra Fettes, Mara Liebig, Aasim Amin, Sheena Sachdeva, Frank Hermann, Eugen Leo.
       BACKGROUND: Resistance to anti-PD-1/PD-L1 therapy is a major unmet need. Growth Differentiation Factor 15 (GDF-15) has been identified as a key resistance factor for anti-PD-1/PD-L1 immunotherapy. Visugromab, a neutralizing anti-GDF-15 antibody, plus the anti-PD-1 antibody nivolumab (V+N) was evaluated in the first-in-human phase 1/2a GDFATHER-01 trial in heavily pretreated participants with locally advanced/metastatic non-squamous non-small-cell lung cancer (nsq NSCLC), urothelial carcinoma (UC), or hepatocellular carcinoma (HCC), stringently defined as anti-PD-1/PD-L1-relapsed/refractory, and showed encouraging objective responses. This analysis reports long-term follow-up of these three phase 2 expansion cohorts of the GDFATHER-01 trial.
    METHODS: Seventy-seven participants with nsq NSCLC (N=22), UC (N=27), and HCC (N=28) received visugromab (10 mg/kg) plus nivolumab (240 mg) every two weeks until disease progression or unacceptable toxicity.
    RESULTS: Objective response rates (RECIST v1.1) were 18.2% for nsq NSCLC (4/22; 95%CI 5.2-40.3), 18.5% for UC (5/27; 95%CI 6.3-38.1), and 14.3% for HCC (4/28; 95%CI 4.0-32.7). Median duration of response (DoR) was 32.2 months (95%CI 5.5-38.0), 28.8 months (95%CI 7.4-39.4), and 19.4 months (95%CI 5.8-39.7; with protracted recruitment), respectively, with 7/13 responses (53.8%) ongoing. Confirmed complete response or complete metabolic response (CR or CMR) among responders was 61.5% (8/13), with 7/8 ongoing. In addition, 46.2% (6/13) of responders achieved a deeper response on V+N per RECIST v1.1 than with the prior anti-PD-(L)1 therapy; median DoR on V+N was 28.8 months (95%CI 7.4-38.0) versus 12.0 months (95%CI 8.0-24.0) on initial anti-PD-1/PD-L1 treatment. V+N was generally well tolerated.
    CONCLUSIONS: In heavily pretreated, advanced/metastatic participants with nsq NSCLC, UC, or HCC who were anti-PD-1/PD-L1-relapsed/refractory, V+N achieved deep and durable objective responses. The observed DoR, depth of response, and CR+CMR rate among responders exceeded those reported for their initial anti-PD-1/PD-L1 therapy. These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti-PD-1/PD-L1 responses, and warrant further exploration in randomized trials.
    REGISTRY: ClinicalTrials.gov, TRN: NCT04725474, Registration date: 25 January 2021; EudraCT, TRN: 2020-002103-19, Registration date 16 Dec 2020.
    Keywords:  Anti–PD-(L)1-relapsed/refractory solid tumors; GDF-15; Hepatocellular carcinoma; Non-squamous non-small-cell lung cancer; Urothelial carcinoma; Visugromab
    DOI:  https://doi.org/10.1186/s13045-026-01818-2
  6. Cancer Rep (Hoboken). 2026 Jul;9(7): e70621
    Investigating the Role of Anti-Leukemia Inhibitory Factor Antibody on Cytokine Profile in a Mouse Model of Breast Cancer.
    Seyed Mohammad Seifati, Hossein Hadinedoushan, Hossein Ansariniya, Fateme Zare.
       BACKGROUND: Leukemia inhibitory factor (LIF), a member of the IL-6 cytokine family, is increasingly recognized as a tumor-promoting factor in breast cancer, where it contributes to immune suppression, tumor progression, and therapy resistance. While neutralizing LIF is an attractive therapeutic approach, little is known about the systemic immunological consequences of targeting this cytokine. AIMSَ: This study aimed to evaluate the effects of active immunization against recombinant LIF protein-designed to elicit endogenous anti-LIF antibodies-on tumor progression and systemic cytokine responses in a murine breast cancer model.
    METHODS AND RESULTS: Female BALB/c mice were immunized with recombinant LIF protein emulsified in Freund's adjuvant to induce anti-LIF antibodies. Tumors were subsequently established by subcutaneous injection of 4T1 breast cancer cells after antibody titers were confirmed. Serum cytokine levels (IFN-γ, TNF-α, IL-6, IL-10, IL-4, and TGF-β) were measured by ELISA, and tumor growth was monitored. Active immunization against LIF significantly inhibited tumor growth compared to controls. Serum analysis revealed that anti-LIF immunization systemically suppressed tumor-induced IL-10 while significantly enhancing IFN-γ levels in tumor-bearing mice. In contrast, IL-4 reduction was only significant in the absence of tumor challenge, and TNF-α levels were generally reduced by the presence of the tumor regardless of immunization.
    CONCLUSION: Our findings suggest that vaccination against LIF can induce endogenous anti-LIF antibody responses, limit tumor progression, and selectively modulate systemic cytokine profiles, particularly through suppression of tumor-induced IL-10 together with enhanced IFN-γ responses in tumor-bearing mice. These findings support further investigation of LIF-targeted immunization as a potential immunotherapeutic strategy in breast cancer.
    Keywords:  active immunization; breast cancer; cytokines; leukemia inhibitory factor; tumor immunity
    DOI:  https://doi.org/10.1002/cnr2.70621
  7. Cell Signal. 2026 Jul 09. pii: S0898-6568(26)00391-8. [Epub ahead of print] 112734
    NSUN2 integrates glucose and one‑carbon metabolism upstream of Rag GTPase-dependent mTORC1 signaling.
    Xueyi Chen, Li Xiao, Yiying Zhou, Zeyu Wu, Xu Xu, Tao Qiu, Rui Chen.
      How glucose and one‑carbon metabolism converge on Rag GTPase-dependent mechanistic target of rapamycin complex 1 (mTORC1) remains poorly defined, particularly in the absence of AMP-activated protein kinase (AMPK). This study mapped an AMPK-independent glucose-response pathway in human cells using CRISPR editing, rescue assays, proteomics, thermal stability analysis, and RNA sequencing. In AMPK-deficient human cells, glucose refeeding rapidly reactivated mTORC1, and proteomics of mTORC1-associated complexes identified NSUN2 as a glucose-associated factor. NSUN2 loss markedly reduced glucose-induced mTORC1 activation, whereas re-expression restored it. Genetic analyses placed NSUN2 upstream of the lysosomal Rag module because constitutively active Rag GTPases bypassed NSUN2 deficiency. Structure-function studies showed that the acute signaling role of NSUN2 was largely independent of its catalytic cysteines, but required an N-terminal nutrient-responsive motif and a predicted S-adenosylmethionine (SAM)-responsive segment. SAM increased the thermal stability of wild-type NSUN2, and proteomics and Immunoprecipitation identified methionine adenosyltransferase 2 A (MAT2A), a SAM-producing enzyme, as a glucose-responsive NSUN2 partner. MAT2A knockout reproduced the signaling defect. Transcriptomics further linked NSUN2 to glucose-responsive programs in proteostasis, secretion, and stress adaptation. These results identify NSUN2 as a noncanonical signaling factor that couples glucose and methyl-donor availability to Rag-dependent mTORC1 control and transcriptional adaptation.
    Keywords:  Glucose sensing; NSUN2; Nutrient signaling; Rag GTPases; S-adenosylmethionine; mTORC1
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112734
  8. Cell Metab. 2026 Jul 07. pii: S1550-4131(26)00235-4. [Epub ahead of print]38(7): 1255-1257
    FGF21 connects ER stress to sulfide signaling to enhance cellular resilience.
    Sarah Hatem, András K Ponti, Christopher Hine.
      Fibroblast growth factor 21 (FGF21) is a stress-induced endocrine hormone that regulates metabolism. Grandl et al. show that FGF21, through its receptor β-klotho (KLB), enhances sulfide signaling and hydrogen sulfide production, strengthening the unfolded protein response and integrated stress response to promote stress resilience, metabolic adaptation, and potentially healthy aging.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.009
  9. Front Biosci (Landmark Ed). 2026 Jun 01. 31(6): 49071
    The Metabolic States of Cancer-Associated Fibroblasts: Targeting Stromal Reprogramming to Impede Tumor Progression and Immune Evasion.
    Zihang Yu, Xuantang Lu, Ruozheng Pi, Xiaonan Zhang, Hanxiang Jian, Xinyue Lin, Wei Wang, Xue Bai.
      Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that drive tumor growth, survival and therapeutic resistance. Although CAFs have long been viewed as a single stromal population, accumulating evidence indicates that they occupy diverse metabolic states shaped by local nutrients and tumor-derived signals. Recent studies across cancer types have described several recurring metabolic programs. In this review, we summarize five dominant CAF metabolic states as a functional, context-dependent framework: glycolytic, oxidative, fatty acid-oxidizing, lipid-rich, and amino acid-remodeling. These states reflect how CAFs adapt to local metabolic conditions. Collectively, CAF metabolic programs are linked to tumor support and immunosuppressive features, highlighting stromal metabolism as a potential therapeutic vulnerability.
    Keywords:  amino acids; cancer-associated fibroblasts; glycolysis; lipid metabolism; metabolic reprogramming; oxidative phosphorylation; tumor microenvironment
    DOI:  https://doi.org/10.31083/FBL49071
  10. Cancer Res. 2026 Jul 07.
    Targeting Cystine Addiction Suppresses Breast Cancer Lung Metastasis.
    Josep Tarragó-Celada, Asad S Mahmood, Yulia Panina, Sakshi Lalwani, Samantha Atkinson, Amy Spicer, Michael Kossifos, Weigang Cai, Ersa Gjelaj, Sharavan Vishaan Venkateswaran, Saidu Sesay, Izadora Furlani, Nathalie Michelle Legrave, Tegan Gilmore, Richard Mitter, Jayanta Bordoloi, Avinash Ghanate, Vincen Wu, Zoltán Takáts, Bin Yan, Alex Dexter, Rory T Steven, Josephine Bunch, George Georgiou, Everett M Stone, Míriam Tarrado-Castellarnau, James I MacRae, Richard J Burt, Mariia Yuneva.
      Metastatic disease remains a major cause of cancer-related mortality. Recent studies suggest that dissemination to other organs comes with metabolic changes that allow the metastasizing cancer cells to adapt to new microenvironments. A deeper knowledge of these specific metabolic features and associated vulnerabilities could lead to the development of more effective therapies against metastasis. We used in vivo and ex vivo models of MYC-driven breast tumorigenesis to explore the key metabolic pathways that change when mammary gland tumor cells metastasize to the lung. Stable isotope-resolved metabolomics, mass spectrometry imaging, and single-cell RNA sequencing demonstrated that mammary gland tumor-derived lung metastases have increased synthesis of glutathione fueled by increased cystine uptake. Metastatic cells relied heavily on the availability of extracellular cysteine or cystine, possibly due to downregulated intracellular cysteine synthesis through the transsulfuration pathway. When combined with focal radiotherapy, the amino acid degrader cyst(e)inase effectively reduced metastatic burden in the lungs. Together, these findings show that targeting cystine/cysteine exploits a metabolic dependency that is unique to metastatic cells and acts as a sensitizer to radiotherapy-induced oxidative stress, offering a promising targeted strategy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3883
  11. J Immunother Cancer. 2026 Jul 09. pii: e015312. [Epub ahead of print]14(7):
    Plasma proteomics predicts pathological complete response and reveals LIF as a potential mediator of resistance to neoadjuvant immunochemotherapy in resectable NSCLC.
    Shoucheng Feng, Ziqing Feng, Songzuo Xie, Yuheng Zhou, Weizhen Sun, Nengqi Lin, Zhichao Lin, Qinglin Wang, Zerui Zhao, Yaobin Lin, Hao Long.
       BACKGROUND: Neoadjuvant immunochemotherapy (nICT) is increasingly used for resectable non-small cell lung cancer (NSCLC), yet a substantial proportion of patients fail to achieve pathological complete response (pCR). Clinically scalable, minimally invasive biomarkers that predict response and point to actionable resistance mechanisms remain needed.
    METHODS: Pretreatment plasma samples collected prior to the first dose were profiled using the Olink proximity extension assay in a Sun Yat-sen University Cancer Center cohort (n=86), randomly split into a training set (n=65) and an internal validation set (n=21). Differentially abundant proteins associated with pCR were identified, and predictive models were developed using logistic regression, random forest, and extreme gradient boosting (XGBoost), followed by internal validation and independent external validation in the Jiangmen Central Hospital cohort (n=46). Survival associations were evaluated by Cox regression. Mechanistic analyses integrated tumor immunohistochemistry/multiplex immunofluorescence, bulk RNA sequencing with immune deconvolution, and functional validation in subcutaneous and orthotopic murine lung cancer models with pharmacologic leukemia inhibitory factor (LIF) blockade.
    RESULTS: Four candidate proteins (LIF, CXCL1, CX3CL1, and NT-3) showed modest single-marker discrimination for pCR (area under the curve (AUC), 0.611-0.673). Multiprotein models improved prediction, with XGBoost achieving the highest performance (training AUC=0.95; internal validation AUC=0.845 (95% CI 0.65 to 1.00); external validation AUC=0.801 (95% CI, 0.57 to 0.93)). SHapley Additive exPlanations analysis identified LIF as the dominant feature negatively associated with pCR probability. Elevated baseline plasma LIF was associated with inferior overall survival (HR=13.003; 95% CI 1.456 to 116.135; p=0.0217) and progression-free survival (HR=3.75; 95% CI 1.362 to 10.327; p=0.0105) after nICT. High LIF tumors exhibited reduced CD8+ T-cell infiltration and suppressed cytotoxic effector programs. In murine models, LIF blockade synergized with immunochemotherapy to enhance antitumor efficacy, restore CD8+ T-cell effector function, and mitigate T-cell exhaustion.
    CONCLUSIONS: Baseline plasma proteomics shows promise for predicting pCR to nICT in resectable NSCLC and nominates LIF as a predictive, prognostic, and therapeutic candidate mediator of resistance. These findings warrant prospective validation and further investigation of LIF-targeted combination strategies in the neoadjuvant setting.
    Keywords:  Biomarker; Immune Checkpoint Inhibitor; Immunotherapy; Lung Cancer
    DOI:  https://doi.org/10.1136/jitc-2026-015312
  12. Nat Commun. 2026 Jul 04.
    CAF-derived PAI-1 serves as an EGFR ligand and fuels KRAS-mutant pancreatic cancer.
    Yu Wang, Chao Liu, Song Gao, Bo Wang, Hongwei Wang, Zijian Shi, Shunjin Xia, Jiayong Li, Xiaofeng Yao, Xiaofan Guo, Jianwei Zheng, Qianqian Zhou, Zhiqiang Chen, Lei Zheng, Qiang Zhang, Jiang Du, Tianxing Zhou, Zhaoyu Zhang, Weijie Song, Lisha Qi, Yalei Wang, Yuh-Pyng Sher, Min Li, Xuan Zhou, Mien-Chie Hung, Yu Ren, Jihui Hao.
      Epidermal growth factor receptor (EGFR) activation contributes to pancreatic cancer etiology, yet anti-EGFR therapy offers minimal clinical benefits in patients with KRAS mutations. We report that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts (CAFs) is selectively elevated in KRAS-mutant tumors and functions as a ligand of EGFR, contributing to resistance to anti-EGFR therapy. Ablation of stromal PAI-1 breaks the CAF-tumor interaction, curbing tumor growth and enhancing the therapeutic efficacy of anti-EGFR therapy in both genetically engineered mouse models and patient-derived xenografts. Mechanistically, KRAS mutation in PDAC activates c-Myc to release IL-1α from PDAC cells to stimulate NF-κB signaling in CAFs to turn on the transcription of PAI-1. PDAC patients with KRAS mutations have higher plasma PAI-1 levels than those with wild-type KRAS. Our findings reveal a mechanism through which CAFs and tumor cells are regulated by the interaction between PAI-1 secreted by CAFs and EGFR on tumor cells. Importantly, the newly identified ligand-receptor interaction of PAI-1-EGFR in the tumor microenvironment of pancreatic cancer may open a new avenue for understanding receptor biology.
    DOI:  https://doi.org/10.1038/s41467-026-75132-3
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