bims-stacyt 2026-06-14 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2026–06–14
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Lactate-Activated GPR132 Signaling Drives a Tumor Microenvironmental Autocrine Metabolic Loop in Kidney Cancer.
Pharmacological inhibition of LIF signaling reverses PD-L1-mediated immune suppression in gastric cancer.
IL-6 Activity is Required for Maximal Catecholamine Release During High-Intensity Exercise in Men.
Tumor-derived sphingosine-1-phosphate shapes angiogenesis in the acidic microenvironment of osteosarcoma via paracrine and autocrine signaling.
Obesity promotes aggressiveness of endometrial cancer via metabolic reprogramming and intercellular crosstalk in the tumor microenvironment.
Inflammatory cytokines induce new cancer dependencies.
Engineering Hypoxia-Lactate-Ca Coupling for Metabolic-Ion Intervention in Cancer Immunotherapy.
GDF15 participates in epithelial cell senescence in radiation-induced lung injury through the ERK1/2-p16 signaling pathway.
Beyond Glucose: Palmitic Acid Influences VEGFA-VEGFR2 Angiogenic Signaling in Müller Glial Cells.

Cancer Res. 2026 Jun 06.

Lactate-Activated GPR132 Signaling Drives a Tumor Microenvironmental Autocrine Metabolic Loop in Kidney Cancer.

Dazhi Wang, Timothy M Horton, Kyutae David Lee, Ifeanyichukwu Chinedu Ogobuiro, Fatemeh Vatankhah, Isadora de Andrade, John C Pisano, Vijay S Thakur, Mia K Gurevich, Sam Taylor, Mohammad Alyamani, Durga Prasad Gannamedi, Daniel G Isom, David B Lombard, Anthony J Griswold, Nima Sharifi, Vanina T Tcheuyap, James Brugarolas, Mark L Gonzalgo, Oleksandr N Kryvenko, Scott M Welford.

Despite the presence of oxygen, tumors frequently preferentially perform fermentative glycolysis, producing lactate and acidifying the tumor microenvironment. Although studies have observed that high concentrations of lactate in the tumor microenvironment help tumors gain a proliferative advantage, a detailed understanding of the molecular mechanisms is needed to uncover strategies to overcome lactate-mediated growth. Here, we investigated how lactate exerts pro-growth effects in clear cell renal cell carcinoma (ccRCC), a highly glycolytic tumor primarily caused by alterations in the von Hippel-Lindau tumor suppressor and constitutive activation of HIF signaling. High lactate concentrations activated GPR132, a lactate sensor highly expressed by ccRCC, which conferred pro-tumor growth signaling by elevating mitochondrial respiration through the ERK/STAT3/JAK2 pathway. Furthermore, GPR132 facilitated the uptake of lactate through elevation of HIF signaling downstream of AKT/mTOR to fuel mitochondrial respiration in a feed-forward manner. Treatment with a small molecule GPR132 antagonist demonstrated the essentiality of GPR132 to support ccRCC growth in vivo. Together, these findings reveal that GPR132 signaling promotes ccRCC by sustaining mitochondrial integrity and elevating lactate import. The crosstalk between lactate and tumor cells is a metabolic vulnerability that can be disrupted by targeting GPR132, providing a potential treatment strategy for ccRCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3236
Transl Oncol. 2026 Jun 08. pii: S1936-5233(26)00185-3. [Epub ahead of print]70 102848

Pharmacological inhibition of LIF signaling reverses PD-L1-mediated immune suppression in gastric cancer.

Cristina Di Giorgio, Silvia Marchianò, Michele Biagioli, Ginevra Lachi, Carmen Massa, Benedetta Sensini, Eleonora Giannelli, Maria Rosaria Sette, Ginevra Urbani, Francesca Paniconi, Luigi Cari, Maria Chiara Monti, Valentina Sepe, Nicola Natalizi, Luigina Graziosi, Eleonora Distrutti, Annibale Donini, Angela Zampella, Stefano Fiorucci.

   INTRODUCTION: Gastric cancer (GC) is a major clinical challenge, characterized by limited response rates to immune checkpoint inhibitors (ICIs) and persistent immune evasion. Leukemia Inhibitory Factor (LIF), an IL-6 family cytokine, reshapes the tumor microenvironment, yet its contribution to PD-L1-mediated immune suppression in GC has not been investigated.
MATERIAL AND METHODS: LIF and PD-L1 expression were quantified in resected GC specimens and matched mucosa by immunohistochemistry and gene expression (Log2), and their associations with clinicopathological variables and survival were evaluated. GC cell lines were exposed to recombinant LIF and to anovel LIF antagonist, LRI-305. Activation of the JAK1/STAT3 pathway, PD-L1 transcription and protein and epithelial-mesenchymal transition (EMT) markers were analyzed. By t-SNE analysis we profiled LIF⁺/PD-L1⁺ cell subsets across myeloid and non-haematopoietic compartments, and by functional assays we have assessed whether LIF blockade modulates T cell activation.
RESULTS: LIF expression was significantly elevated in GC tissues and correlates with poor prognosis and increased PD-L1 levels. LIF promotes immune escape by activating the JAK1/STAT3 pathway, leading to transcriptional upregulation of PD-L1 and enhancement of EMT. The t-SNE analysis revealed that LIF⁺/PD-L1⁺ myeloid and non-hematopoietic cells were enriched in the neoplastic mucosa. Pharmacological blockade of LIF signaling effectively suppressed STAT3 phosphorylation and downregulated PD-L1 expression. LRI-305 treatment partially restored immune activation signatures, supporting its potential as a therapeutic adjuvant to ICIs.
DISCUSSION: LIF/STAT3 enhances PD-L1 expression and participate to GC immune evasion. Targeting LIF signaling could be a strategy to overcome resistance to immunotherapy.

Keywords:  Checkpoint blockade; Gastric cancer; Immune evasion; Leukemia inhibitory factor; PD-L1; STAT3; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.tranon.2026.102848
Mol Metab. 2026 Jun 10. pii: S2212-8778(26)00079-7. [Epub ahead of print] 102395

IL-6 Activity is Required for Maximal Catecholamine Release During High-Intensity Exercise in Men.

Andreas K Ziegler, Tim Schauer, Sara F Myrup, Gerrit van Hall, Bente K Pedersen, Jesper F Christensen, Helga Ellingsgaard.

  High-intensity exercise triggers a coordinated activation of metabolic, endocrine, and immune pathways, yet the mechanisms integrating these responses remain incompletely understood. Interleukin-6 (IL-6), released during exercise, has been proposed as a systemic signal linking skeletal muscle activity to whole-body stress responses. We tested whether exercise-induced IL-6 is required for full sympathoadrenal activation and immune cell mobilization during intense exercise in humans. Healthy young men received the IL-6 receptor (IL-6R) antibody tocilizumab prior to high-intensity interval exercise. IL-6R blockade reduced circulating epinephrine by ∼50%, lowered plasma glucose levels, and attenuated lactate accumulation, resulting in a smaller decline in blood pH. Immune cell mobilization was selectively impaired, with reduced recruitment of lymphocytes, CD8+ T cells, CD56ˆbright natural killer (NK) cells, monocytes, neutrophils, and dendritic cells, while CD4+ T cells, CD56ˆdim NK cells, and B cells were unaffected. Although upstream hypothalamic-pituitary-adrenal (HPA)-axis hormones corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) were unchanged, adrenocorticotropic hormone (ACTH) was significantly reduced and associated with pH and catecholamine responses in the control condition. A lower lactate-to-pyruvate ratio during IL-6R blockade suggests enhanced pyruvate oxidation as a potential upstream mechanism. These findings position IL-6 as an integrative metabolic signal that mediates organ crosstalk and amplifies the HPA and sympathoadrenal response during high-intensity exercise. By linking skeletal muscle metabolic stress to endocrine activation, glucose regulation, and immune cell mobilization, IL-6 appears to coordinate the complex systemic fight-or-flight response to intense physical exertion.

Keywords:  Epinephrine; Exercise; Glucose; Immune System; Interleukin-6; Tocilizumab

DOI:  https://doi.org/10.1016/j.molmet.2026.102395
Front Cell Dev Biol. 2026 ;14 1831997

Tumor-derived sphingosine-1-phosphate shapes angiogenesis in the acidic microenvironment of osteosarcoma via paracrine and autocrine signaling.

Sofia Avnet, Nicolò Bozzini, Phuong-Nhi Nguyen, Maria Veronica Lipreri, Francesca Perut, Nicola Baldini, Margherita Cortini.

   Introduction: Tumor-associated angiogenesis is a critical driver of tumor progression and is frequently characterized by excessive branching and structural disorganization. These abnormalities arise from dynamic interactions between tumor cells and the microenvironment, where metabolic stressors such as hypoxia and extracellular acidosis promote the release of pro-angiogenic factors. Among these, sphingosine-1-phosphate (S1P) has emerged as a key bioactive lipid involved in vascular development. We previously demonstrated that acidosis promotes sphingomyelin turnover and S1P secretion in osteosarcoma cells, enhancing tumor cell survival and migration. In this study, we investigated the role of S1P in osteosarcoma-associated angiogenesis and the contribution of tumor acidosis to this process.
Methods: Matrigel®-based angiogenesis assays, HUVEC cultures, 3D osteosarcoma spheroids, and microfluidic systems were employed to evaluate endothelial sprouting and tubulogenesis. S1P signaling was pharmacologically inhibited using the FDA-approved S1P modulator FTY720 (Fingolimod). Conditioned media from osteosarcoma spheroids cultured under neutral or acidic conditions were analyzed for their pro-angiogenic activity. Soluble and extracellular vesicle-associated angiogenic mediators were also assessed.
Results: S1P dose-dependently impaired endothelial tubulogenesis while strongly promoting endothelial sprouting. Conditioned media derived from acid-stimulated osteosarcoma spheroids significantly increased endothelial tubule length and branching compared with conditioned media from spheroids maintained at neutral pH. These effects were markedly reduced by FTY720 treatment. Furthermore, tumor-derived S1P activated autocrine signaling in osteosarcoma cells, enhancing the secretion of soluble and extracellular vesicle-associated pro-angiogenic mediators, including bFGF and the TGF-β co-receptor Endoglin (CD105).
Discussion: These findings identify a previously unrecognized acidosis-S1P axis that contributes to angiogenic remodeling in osteosarcoma. Our results highlight the multifaceted role of S1P in regulating endothelial behavior and suggest that targeting S1P signaling may represent a promising strategy to disrupt pathological neoangiogenesis in osteosarcoma.

Keywords:  3D tumor models; acidosis; angiogenesis; osteosarcoma; sphingosine-1-phosphate; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2026.1831997
Cancer Lett. 2026 Jun 05. pii: S0304-3835(26)00412-X. [Epub ahead of print]656 218649

Obesity promotes aggressiveness of endometrial cancer via metabolic reprogramming and intercellular crosstalk in the tumor microenvironment.

Yu Chen, Yijin Fang, Guozhi Zhao, Yuanqun Zhou, Dong-Hua Yang, Jian Han, Ying Zheng.

  Endometrial cancer is one of the most prevalent malignancies of the female reproductive system, and the global rising prevalence of obesity has further increased its incidence and poor clinical prognosis. Although obesity is recognized as a critical modifiable risk factor for endometrial cancer, it remains unclear whether and how obesity drives tumor initiation and progression by modulating the tumor microenvironment at single-cell resolution. Using a genetic mouse model with pten conditional knockout in the uterine endometrium, clinical samples from endometrial cancer patients, and single-cell RNA sequencing from 10 endometrial tumor samples, we delineated a comprehensive single-cell atlas of endometroid endometrial cancer altered by obesity. The results reveal a unique SOX9+LGR5+ epithelial subpopulation exhibiting cancer stem cell features, which establishes an intratumoral estrogen-signaling circuit. Tumor-associated macrophages and NK/T cells undergo profound metabolic reprogramming toward pro-tumor and immunosuppressive phenotypes. Fibroblasts exhibit remarkable phenotypic and metabolic rewiring within a lipid-rich microenvironment, facilitating extracellular matrix remodeling. Emerging endothelial subsets drive angiogenesis and vascular dysfunction, fostering intratumoral hypoxia and cancer cell metastasis. These components engage in extensive intercellular crosstalk centered on tumor-associated macrophages, forming a self-reinforcing network that drives immunosuppression, stemness maintenance, cell migration, and aberrant angiogenesis. Our findings highlight that obesity-induced tumor microenvironment remodeling and metabolic communication constitute key mechanisms underlying tumor aggressiveness of obesity-related endometrial cancer, providing novel mechanistic insights and potential therapeutic targets for clinical intervention.

Keywords:  Endometrial cancer; Metabolic reprogramming; Obesity; Single-cell RNA sequencing; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.canlet.2026.218649
Nat Genet. 2026 Jun;58(6): 1353-1367

Inflammatory cytokines induce new cancer dependencies.

Collins K Cheruiyot, Sarah Y Kim, Juan Dubrot, Sarah K Lane-Reticker, Alex Miranda, Ashwin V Kammula, Jonathan J Perera, Peter P Du, Cun Lan Chuong, Rachel A Fetterman, Nelson H Knudsen, Aiping Jiang, Juliette S M T Suermondt, Lomax F Pass, Cong Fu, Meng-Ju Wu, Lei Shi, Seth Anderson, Audrey J Muscato, Omar I Avila, Ian C Kohnle, Emily A Kessler, Hans W Pope, Sarah G Noel, Kira E Olander, Jooho Chung, Kayla J Colvin, Nabeel Bardeesy, Kathleen B Yates, Robert T Manguso.

Tumor cells respond and adapt to environmental stresses that facilitate growth in hostile environments, including cytokine-mediated inflammation elicited by antitumor immunity and enhanced by immune checkpoint blockade (ICB). However, cytokine responses also induce transcriptional and cell-state changes that may predispose tumor cells to new vulnerabilities, which remain poorly explored. Here we performed in vitro genome-scale CRISPR loss-of-function screens in eight cancer models exposed to interferon-γ (IFNγ), interferon-β or tumor necrosis factor to map inflammation-induced genetic vulnerabilities. We identified members of the glycosylphosphatidylinositol (GPI) transamidase complex and the lipid phosphatase FITM2 as interferon-specific cancer dependencies. Tumor-specific deletion of GPI transamidase subunits or FITM2 markedly enhanced response to ICB in vivo. By integrating functional genomics, metabolomics and pharmacologic perturbation of downstream stress pathways, we found that loss of FITM2 predisposed cancer cells to IFNγ-driven endoplasmic reticulum and oxidative stress, culminating in paraptosis-like cell death. Collectively, these findings identify tumor-intrinsic dependencies governing responses to inflammatory cytokines.

DOI: https://doi.org/10.1038/s41588-026-02614-x
ACS Appl Mater Interfaces. 2026 Jun 10.

Engineering Hypoxia-Lactate-Ca Coupling for Metabolic-Ion Intervention in Cancer Immunotherapy.

Li Ma, Ruyu Zhao, Lunhui Lai, Yuanhao Zhang, Guan Zhang, Zewen Wang, Fang Cheng, Lianhui Wang.

  Lactate-rich and hypoxic tumor microenvironments (TMEs) impose a major barrier to cancer immunotherapy by sustaining metabolic immunosuppression. Although blockade of lactate export can reduce extracellular lactate burden, hypoxia-driven glycolysis continuously replenishes lactate, limiting the benefit of efflux inhibition alone. More importantly, lactate export blockade traps lactate inside tumor cells, creating an intracellular metabolic state that increases susceptibility to Ca2+-associated stress. Herein, we report a TME-activated nanoreactor (CZCH) that exploits this lactate trapping effect to amplify Ca2+-mediated immunogenic stress for tumor immunomodulation. Upon acidic activation after tumor-cell internalization, CZCH simultaneously alleviates hypoxia, blocks lactate efflux, and releases Ca2+, thereby coupling intracellular lactate trapping with ionic stress amplification. This mechanism is further reinforced by Ca2+-derived oxidative stress, which together drives severe mitochondrial dysfunction and immunogenic cell death. As a result, CZCH reshapes the immunosuppressive TME by promoting dendritic cell maturation and repolarizing macrophages toward an M1-like phenotype. In vivo, CZCH suppresses primary tumor growth, reduces pulmonary metastasis, and enhances the responsiveness of distant tumors to αPD-L1 blockade through systemic antitumor immune activation. These findings establish lactate trapping-enabled Ca2+ sensitization as a therapeutically actionable mechanism and provide a nanomaterial strategy for metabolic-ion intervention in cancer immunotherapy.

Keywords:  Calcium overload; Immune checkpoint blockade; Immunogenic cell death; Lactate metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1021/acsami.6c06604
PLoS One. 2026 ;21(6): e0350042

GDF15 participates in epithelial cell senescence in radiation-induced lung injury through the ERK1/2-p16 signaling pathway.

Jing Liu, Dongyang Lv, Hengjiao Wang, Defu Yang, Ying Xu, Ying Yan.

OBJECTIVE: Radiation-induced lung injury (RILI) is a common complication of thoracic radiotherapy that can compromise treatment outcomes and reduce the quality of life of cancer patients. Cellular senescence is increasingly recognized as an important biological process in the development of RILI. This study aimed to identify senescence-associated molecules involved in RILI and to investigate their potential mechanisms of action.
METHODS: Bioinformatics analysis was performed by integrating differential gene expression profiles from a RILI-related GEO dataset with a senescence-related gene set, which identified growth differentiation factor 15 (GDF15) as a candidate molecule of interest. A rat model of RILI was established, and inflammatory injury and fibrosis were evaluated by hematoxylin and eosin (HE) staining and Masson's trichrome staining. DNA damage was assessed by γH2AX immunofluorescence. Senescence-associated changes were evaluated by senescence-associated β-galactosidase (SA-β-gal) staining and detection of p53, p21, p16, and GDF15 expression by Western blot. In addition, in vivo and in vitro experiments were performed to further explore the potential mechanism associated with GDF15 in radiation-induced epithelial senescence.
RESULTS: Bioinformatics analysis identified GDF15 as a prominently upregulated senescence-related gene in RILI. In irradiated rat lungs, γH2AX expression was significantly increased, accompanied by inflammatory infiltration, fibrotic changes, and upregulation of senescence-associated markers. SA-β-gal staining further supported the presence of radiation-induced senescence in vivo. Similar findings were observed in irradiated BEAS-2B cells. Mechanistic experiments showed that GDF15 knockdown attenuated radiation-induced senescence and downregulated the expression of p-ERK1/2 and downstream p16, while ERK1/2 inhibition reduced senescence-associated β-gal staining and p16 expression. These findings suggest that radiation-induced GDF15 may contribute to epithelial cell senescence during RILI, potentially through the ERK1/2-p16 signaling pathway.
CONCLUSION: Our findings suggest that GDF15 is upregulated in response to ionizing radiation and may participate in epithelial cell senescence during the development of RILI. This process appears to be associated with the ERK1/2-p16 signaling pathway. These results provide additional insight into the molecular mechanisms underlying RILI and suggest that GDF15 may represent a potential target for future therapeutic intervention.

DOI: https://doi.org/10.1371/journal.pone.0350042
Int J Mol Sci. 2026 Jun 05. pii: 5144. [Epub ahead of print]27(11):

Beyond Glucose: Palmitic Acid Influences VEGFA-VEGFR2 Angiogenic Signaling in Müller Glial Cells.

Jesus Silvestre Albert-Garay, Alan E Medina Arellano, Karla Hernández-Fonseca, Tania Medina-Sánchez, Matilde Ruiz-Cruz, Lenin Ochoa-de la Paz.

  Research on diabetic retinopathy (DR) usually emphasizes hyperglycemia and other causes like dyslipidemia, which are still not well understood. This study examined the effects of palmitic acid (PA) exposure, alone and combined with high glucose (G25), on Müller Glial Cell (MGC) dysfunction and angiogenic signaling. Primary MGC cultures were treated with G25 (25 mM), PA (250 µM), or PA + G25 for 24 and 48 h, followed by assessments of cell viability and analysis of the Vascular Endothelial Growth Factor (VEGFA)/VEGFA receptor 2 (VEGFR2) pathway through immunofluorescence, Western blot, and ELISA. Additionally, Gaussian mixture models (GMMs) were used to identify phenotypic subpopulations based on fluorescence intensity. The results showed that while hyperglycemia did not cause significant changes, PA and PA + G25 induced apoptosis-related cell death and significantly increased the expression of VEGFA, VEGFR2, HIF-α, and SP1. Although broad phenotypic diversity was observed at 24 h, by 48 h, a distinct shift towards an angiogenic phenotype was noted, with significantly elevated VEGFA/VEGFR2 levels. In summary, this research demonstrates that PA acts as a critical inducer of an angiogenic secretory phenotype in MGCs, indicating that lipid-mediated signaling plays a vital role in neovascularization in DR, possibly independent of glucose levels.

Keywords:  Müller glial cell; VEGFA; VEGFR2; diabetic retinopathy; palmitic acid

DOI:  https://doi.org/10.3390/ijms27115144