bims-stacyt 2026-07-19 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2026–07–19
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
Blockade of the GDF15/GFRAL Axis: Translational Advances in Cachexia, Immune Suppression, and Beyond.
Macrophage-Myocyte Cross Talk Induces M1 Polarization and Inflammatory Cytokine Production During Cancer Cachexia.
Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation.
Metabolic Symbiosis Between Cancer Cells and Endothelial Cells: A Key Driver of Tumor Angiogenesis.
Metformin triggers ATF4-mediated UPRmt and COX-2 inflammation in adipocytes.
Hypoxia-driven tumor immune escape: mechanisms and therapeutic opportunities.
Ammonia metabolic reprogramming in the tumor microenvironment: emergence of an immunosuppressive niche.
Metabolic adaptations of the tumor macroenvironment and their role in cancer progression and survivorship.
Immunometabolic Stress and Immune Suppression in Clear-Cell Renal Cell Carcinoma: Perspectives in Therapeutic Strategy.

Mol Metab. 2026 Jul 17. pii: S2212-8778(26)00106-7. [Epub ahead of print] 102422

Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.

Emma Frank, Kaspar W Persson, Pauline Morigny, Zakarias Kefil Jensen Ogueboule, Tang Cam Phung Pham, Jonas R Knudsen, Maria Rohm, Lykke Sylow, Steffen H Raun.

   PURPOSE: Cancer cachexia is a life-threatening complication of advanced malignancies, driven by profound systemic metabolic reprogramming and anorexia. Insulin action is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between weight loss, food intake, and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies.
METHODS: We assessed metabolic rewiring by temporal evaluation of glucose tolerance and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as healthy mice undergoing food restriction.
RESULTS: Cachectic C26- and KPC-tumor mice showed increased glucose tolerance compared to non-tumor-bearing control mice, and non-cachectic tumor-bearing mice. Increased glucose tolerance appeared prior to overt muscle loss, independent of tumor size and changes in food intake. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-cancer mice with anorexia compared to weight stable C26-cancer mice and control mice. This increase was associated with enhanced AKT signaling. Food restriction in healthy mice increased glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling.
CONCLUSIONS: Our findings suggest that glucose hypermetabolism appears prior to overt weight loss in pre-clinical cachexia, whereas late-stage cachexia with anorexia increased skeletal muscle insulin responsiveness. This highlights AKT signaling as a key node connecting nutrient status with muscle metabolism in cancer cachexia.

Keywords:  Cancer cachexia; food restriction; glucose metabolism; insulin sensitivity; muscle

DOI:  https://doi.org/10.1016/j.molmet.2026.102422
Curr Drug Targets. 2026 Jul 07.

Blockade of the GDF15/GFRAL Axis: Translational Advances in Cachexia, Immune Suppression, and Beyond.

Qi Zhou, Yan Yang.

   INTRODUCTION: Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the transforming growth factor β (TGF-β) superfamily. In normal physiology, GDF15 is expressed in multiple tissues at low concentrations. However, its expression significantly increases following many pathological conditions, such as tissue injury, inflammation, mitochondrial dysfunction, and cancer. GDF15 has emerged as a significant biomarker and a promising therapeutic target since the identification of its central nervous system-restricted receptor, Glial cell line-derived neurotrophic factor family receptor α-like (GFRAL)-REarranged during Transfection proto-oncogene (RET).
METHODS: We conducted a narrative review of the published literature on the molecular mechanisms of GDF15, with special focus on interventional studies using anti-GDF15 drugs. This review highlights the therapeutic potential of blockade of the GDF15/GFRAL axis based on current preclinical and clinical data.
RESULTS: GDF15 is a multifaceted factor that exerts a central role in regulating energy balance, demonstrating context-dependent effects. It acts as a key mediator of anorexia and weight loss in cancer cachexia. Furthermore, GDF15 contributes to the remodeling of the tumor immune microenvironment by inhibiting immune cell functions. Therapeutic strategies developed based on this, such as GDF15 antagonists, neutralizing antibodies, GFRAL receptor fusion proteins, as well as the combined application of GDF15-targeted drugs and immune checkpoint inhibitors, have yielded promising results in clinical trials. We also include a discussion of the potential limitations in the development of anti-GDF15 drugs.
DISCUSSION: GDF15-targeted drugs have shown potential benefits in reversing cancer cachexia and may enhance anti-tumor immunity, but this remains to be confirmed in larger, controlled studies. The primary challenge in targeting GDF15 lies in the complexity and context-dependent nature of its biological functions.
CONCLUSION: GDF15 represents a highly compelling therapeutic target for metabolic and oncological diseases. Overcoming the challenges posed by its biological complexity is essential to successfully translating GDF15-targeted strategies into precision medicine applications.

Keywords:  GDF15 receptor; Growth differentiation factor-15 (GDF-15); glial-derived neurotro

DOI:  https://doi.org/10.2174/0113894501465574260629112344
Mediators Inflamm. 2026 ;2026(1): e6461737

Macrophage-Myocyte Cross Talk Induces M1 Polarization and Inflammatory Cytokine Production During Cancer Cachexia.

Se-Eun Bae, Miyong Yun, Min Ju Kang, Sang Woo Woo, Do Won Kim, Eun-Ok Kim, Hyeon Soo Kim.

Cancer cachexia (CC) significantly reduces survival in patients with cancer, and intramuscular inflammation plays an important role in disease progression. Macrophages, as key mediators of the innate immune response, contribute to muscle inflammation by secreting pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), in response to various stimuli. Despite their importance, the mechanisms of macrophage polarization within the cachectic skeletal muscle and the subsequent impacts on muscle inflammation remain poorly understood. In this study, we used a murine model of CC to explore the interaction between macrophages and myocytes during muscle inflammation. Our results demonstrate that cachectic myocytes recruit M1-polarized macrophages that amplify local inflammation via the secretion of IL-1β, IL-6, and TNF-α. These findings underscore the pivotal role of macrophage-derived cytokines in the pathogenesis of cancer-induced muscle inflammation and suggest that targeting macrophage-driven inflammatory pathways may be an effective therapeutic strategy for mitigating muscle wasting in CC.

DOI: https://doi.org/10.1155/mi/6461737
Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2537017123

Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation.

Kristof Torkenczy, Lucas C Reineke, Sean W Dooling, Benjamin W Henderson, Benjamin Yang, Dongze He, Richard M Myers, Peter Walter, Stefka Tyanova, Mauro Costa-Mattioli.

  Persistent activation of the integrated stress response (ISR) is a central driver of cognitive decline in both neurodevelopmental and neurodegenerative disorders. However, the cell type-specific mechanisms underlying these deficits remain poorly understood. By integrating single-cell RNA-seq and single-cell assay for transposase-accessible chromatin sequencing, we generated a brain ISR atlas using Ppp1r15bR658C mice, a clinically relevant model of intellectual disability characterized by selective and persistent ISR activation. We find that distinct brain cell types differentially engage transcriptional and chromatin remodeling programs. Notably, selective deletion of the major ISR downstream effector ATF4 in GABAergic neurons, but not in glutamatergic neurons, exacerbates ISR-mediated cognitive decline in Ppp1r15bR658C mice, demonstrating that different neuronal subtypes rely on distinct ISR effectors. We define a molecular single-cell signature of persistent ISR activation that serves as a metric of ISR-mediated cellular vulnerability and as a biomarker for cognitive dysfunction across human cognitive disorders. These findings demonstrate that cell type-specific responses drive cognitive dysfunction during persistent ISR activation.

Keywords:  cellular homoeostasis; cognitive decline; single-cell ATAC-sequencing; single-cell RNA-sequencing

DOI:  https://doi.org/10.1073/pnas.2537017123
Adv Exp Med Biol. 2026 ;1501 165-189

Metabolic Symbiosis Between Cancer Cells and Endothelial Cells: A Key Driver of Tumor Angiogenesis.

Jacinta Serpa.

  This chapter explores the critical role of angiogenesis in cancer, focusing on the metabolic processes involved in angiogenesis, particularly the metabolic remodeling of endothelial cells (ECs) and the symbiosis between cancer cells and ECs, which drive vascular development. Key topics include the influence of hypoxia and oxidative stress, and the reliance on different metabolic sources on EC function, as well as how various pro-angiogenic factors contribute to tumor vascularization. The importance of metabolic flexibility in ECs and its implications for cancer treatment will also be highlighted.

Keywords:  Angiogenesis; Cancer cells; Endothelial cells (ECs); Metabolic remodeling; Metabolic symbiosis; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-3-032-12166-0_6
Biochim Biophys Acta Mol Cell Res. 2026 Jul 16. pii: S0167-4889(26)00090-X. [Epub ahead of print] 120191

Metformin triggers ATF4-mediated UPRmt and COX-2 inflammation in adipocytes.

Juthakorn Poothong, Chutipong Chiamkunakorn, Wichit Suthammarak, Teva Phanaksri, Prasert Auewarakul, Jing Yong, Randal J Kaufman.

  Metformin is the most common drug for type 2 diabetes due to its action to improve insulin sensitivity and enhance glucose uptake in tissues, including adipose tissue. As a mitochondrial complex I inhibitor, treatment with metformin may cause deleterious effects. Here, we demonstrated that treatment of adipocytes 3 T3-L1 cells with a high concentration of metformin (10 mM) led to increased reactive oxygen species (ROS) accumulation and triggered the mitochondrial unfolded protein response (UPRmt), as revealed by increased mRNA expression of UPRmt markers (mtHSP70, Lonp1, and FGF21). High-concentration metformin also induced COX-2 inflammation, as indicated by increased NF-κB phosphorylation and cyclooxygenase-2 (COX-2) expression. By contrast, a lower concentration (1.25 mM) showed no effects. We found that ATF4 was selectively upregulated and was required for UPRmt and COX-2 inflammation induced by metformin. Interestingly, we showed that the integrated stress response inhibitor (ISRIB) effectively inhibited ATF4, mitigated metformin-induced UPRmt, and reduced NF-κB/COX-2 expression. Taken together, our findings point to the undesirable effect of the high-concentration metformin in adipocytes.

Keywords:  ATF4; COX-2; ISRIB; Metformin; ROS; UPR(mt)

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120191
Front Immunol. 2026 ;17 1893099

Hypoxia-driven tumor immune escape: mechanisms and therapeutic opportunities.

Hongran Qin, Shuqiang Yang, Jiawei He, Meijia Zhao, Luqian Zhao, Jingjing Wang, Xiulin Jiang, Xiaowen Chen, Xin Xu.

  Hypoxia is a common feature of solid tumors and a major driver of tumor immune escape. It arises from abnormal tumor vasculature and rapid tumor growth, leading to persistent or fluctuating oxygen deprivation within the tumor microenvironment. Under hypoxic conditions, hypoxia-inducible factors, especially HIF-1α and HIF-2α, activate transcriptional programs that support tumor survival, angiogenesis, glycolytic metabolism, invasion, and therapy resistance. Beyond these tumor-intrinsic effects, hypoxia also reshapes antitumor immunity by suppressing CD8+ T cells, natural killer cells, and dendritic cell antigen presentation, while promoting regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. These changes establish a strongly immunosuppressive microenvironment and reduce the efficacy of immunotherapy. Hypoxia-driven immune escape is mediated by several interconnected mechanisms. HIF signaling promotes lactate accumulation, acidosis, adenosine signaling, PD-L1 expression, myeloid cell recruitment, and T cell exhaustion. In addition, emerging evidence indicates that RNA modifications, including m6A and ac4C, provide a post-transcriptional regulatory layer that links hypoxia signaling with immune checkpoint regulation, chemokine production, myeloid metabolism, and HIF-1α translation. Therapeutically, targeting hypoxia-related pathways may improve antitumor immunity, but single-agent approaches are often insufficient because hypoxic tumors use multiple overlapping escape mechanisms. Rational combinations involving HIF inhibitors, metabolic intervention, immune checkpoint blockade, cell therapy optimization, and RNA epitranscriptomic targeting may provide more effective strategies. In this review, we summarize how hypoxia coordinates metabolic barriers, immune remodeling, checkpoint activation, and RNA modification-dependent regulation to drive tumor immune escape, and discuss future directions for targeting the hypoxia-metabolism-immune axis in cancer immunotherapy.

Keywords:  HIF-1α; RNA epitranscriptomics; cancer immunotherapy; hypoxia; immune checkpoints; immune escape; metabolic reprogramming; myeloid-derived suppressor cells

DOI:  https://doi.org/10.3389/fimmu.2026.1893099
Front Cell Dev Biol. 2026 ;14 1826809

Ammonia metabolic reprogramming in the tumor microenvironment: emergence of an immunosuppressive niche.

Zihao Ye, Hao Wu, Zhanhao Li, Ruizhe Ye, Yingliang Rao, Bin Liu, Baoshan Gao.

  Metabolic reprogramming within the tumor microenvironment plays a pivotal role in tumor proliferation, progression, and immune evasion. Cancer cells exhibit altered lipid, glucose, and amino acid metabolism to adapt to hostile conditions such as hypoxia and nutrient deprivation. Particularly, ammonia metabolism has emerged as a critical aspect of tumor metabolic reprogramming. Oncogene mutations, such as those in c-MYC, KRAS, and p53, regulate key enzymes involved in amino acid metabolism, which in turn affects tumor cell survival and proliferation. Elevated ammonia levels in the TME (Tumor Microenvironment) not only provide essential nitrogen for cell growth but also impair immune cell function, including T cells and natural killer cells, contributing to immune evasion. High ammonia concentrations suppress T cell activation and promote exhaustion, while interfering with natural killer cell cytotoxicity by hindering perforin maturation. Moreover, ammonia accumulation fosters an immunosuppressive microenvironment, influencing cytokine secretion and facilitating tumor metastasis. Targeting ammonia metabolism, in combination with immune checkpoint inhibitors, presents a promising therapeutic strategy to enhance immune responses and inhibit tumor progression. This review consolidates recent findings on the role of ammonia metabolism in the TME, highlighting its potential as a therapeutic target to improve cancer treatment outcomes.

Keywords:  SLC (solute carrier family); TME (tumor microenvironment); ammonia metabolism; cancer; metabolic reprogram

DOI:  https://doi.org/10.3389/fcell.2026.1826809
Genes Dev. 2026 Jul 17.

Metabolic adaptations of the tumor macroenvironment and their role in cancer progression and survivorship.

Devesh Raizada, Ana P Gomes.

  Cancer progression is shaped not only by tumor-intrinsic programs and the local microenvironment but also by profound metabolic rewiring of the host at the organismal scale. Tumors engage in dynamic cross-talk with distant organs, immune and neuroendocrine networks, and systemic nutrient pools, generating a metabolically permissive macroenvironment that fuels tumor growth, supports metastatic dissemination, and undermines therapeutic efficacy. In this review, we synthesize emerging evidence showing how cancer-driven systemic metabolic remodeling reshapes glucose, lipid, and protein metabolism, perturbs immune and hematopoietic homeostasis, and hijacks neuroendocrine circuits governing energy balance and stress responses. We further highlight how these adaptations fuel cellular energetics within tumor cells as well as promote premetastatic niche formation, immune evasion, and therapy resistance, while leaving durable metabolic and inflammatory scars that accelerate biological aging and compromise long-term health in cancer survivors. Together, these findings position tumor-host metabolic cross-talk as a central, targetable axis in cancer biology with broad implications for therapy and survivorship care.

Keywords:  cancer progression; metabolism; tumor macroenvironment

DOI:  https://doi.org/10.1101/gad.353830.126
Int J Mol Sci. 2026 Jul 04. pii: 6021. [Epub ahead of print]27(13):

Immunometabolic Stress and Immune Suppression in Clear-Cell Renal Cell Carcinoma: Perspectives in Therapeutic Strategy.

Tuong-Vi Nguyen, Tien Hsu.

  Solid tumors frequently experience hypoxia during tumor progression, resulting in profound metabolic alterations. This phenomenon is particularly pronounced in clear-cell renal cell carcinoma (ccRCC) because of loss of the von Hippel-Lindau (VHL) tumor suppressor gene and constitutive activation of hypoxia-inducible factor (HIF) signaling. ccRCC is the most common subtype of kidney cancer, and durable therapeutic responses remain limited despite advances in immune checkpoint inhibition. Owing to its strong pseudohypoxic phenotype and extensive metabolic rewiring, ccRCC is widely regarded as a metabolic disease. These alterations generate a unique immune landscape characterized by abundant immune-cell infiltration together with profound T-cell dysfunction and exhaustion. This paradoxical "immune-hot yet immunosuppressed" phenotype is largely driven by hypoxia-associated immunometabolic reprogramming within tumor cells and the tumor microenvironment (TME). Several metabolic pathways are critically involved in this process, including lactate acidosis, arginine (Arg) depletion, tryptophan (Trp) depletion, kynurenine (Kyn)-mediated T-cell exhaustion, and adenosine-driven immune suppression. This review summarizes the current understanding of hypoxia-driven immunometabolic interactions in ccRCC and discusses how targeting these pathways may improve future therapeutic strategies against this aggressive malignancy.

Keywords:  clear-cell renal cell carcinoma; hypoxia; immune suppression; immunometabolism; kynurenine pathway; metabolic reprogramming

DOI:  https://doi.org/10.3390/ijms27136021