bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2026–06–28
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Transcription Factor ATF4 Deletion Reprograms Glucose Metabolism in Clear Cell Renal Cell Carcinoma.
  2. ATF4 and CHOP coordinate endoplasmic reticulum stress-responsive gene programs through enhancer activation and chromatin looping.
  3. Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.
  4. Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.
  5. Beyond a waste product: lactate as a master metabolite dictating anti-tumor T-cell fate.
  6. A novel EGR1-driven GLUL/mTOR axis regulates macropinocytosis-mediated crosstalk in pancreatic stellate cell-cancer metastasis.
  1. Cancers (Basel). 2026 Jun 16. pii: 1953. [Epub ahead of print]18(12):
    Transcription Factor ATF4 Deletion Reprograms Glucose Metabolism in Clear Cell Renal Cell Carcinoma.
    Yuling Chi, Qiuying Chen, Eduardo Mere Del Aguila, Steven S Gross, John A Wagner, Shannon M Reilly, David M Nanus, Lorraine J Gudas.
      Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Human ccRCCs have increased glycolytic metabolism and decreased mitochondrial oxidative metabolism relative to normal kidneys. Our research using human RCC4 ccRCC cells and a murine model of ccRCC, TRACK (TRAnsgenic model/Cancer/Kidney), in which a triple-mutant (P402A, P564A, N803A) human HIF1α is selectively expressed in proximal tubule cells (PTCs), revealed highly induced ATF4, a stress-responsive transcription factor. We then investigated the role of ATF4 in the metabolic changes in ccRCC. Methods: We performed comprehensive analysis of the ccRCC Cancer Genomics Atlas (TCGA) data. We deleted ATF4 in PTCs of TRACK mice and human RCC4 cells. We conducted genome-wide transcriptomic and untargeted metabolomic studies of cortices of WT and CGERA∆T (TRACK mice with PTC-specific ATF4-knockout (KO)) mice and performed glucose isotopologue tracing in parental and ATF4 KO RCC4 cells. Results: Analysis of TCGA data showed increased mRNAs of enzymes in glycolysis and reduced mRNAs of enzymes in the TCA cycle. Transcriptomic and metabolomic studies demonstrated that ATF4 deletion suppressed glycolysis and enhanced TCA cycle metabolism in CGERA∆T versus WT cortices. Glucose isotopologue tracing showed that ATF4 deletion altered glycolysis pathway metabolite levels and shifted glucose metabolism towards the TCA cycle, evidenced by increased intracellular [13C2]citrate in RCC4-ATF4 KO cells. Using the Seahorse XFe96 analyzer we also showed reduced glycolytic capacity and reserve in RCC4-ATF4 KO cells. Conclusions: Collectively, our results demonstrate that ATF4 regulates glycolysis in ccRCC, supporting ATF4 as a therapeutic target.
    Keywords:  ATF4; clear cell renal cell carcinoma (ccRCC); glycolysis; metabolomics; mitochondrial oxidative phosphorylation
    DOI:  https://doi.org/10.3390/cancers18121953
  2. Nucleic Acids Res. 2026 Jun 22. pii: gkag641. [Epub ahead of print]54(12):
    ATF4 and CHOP coordinate endoplasmic reticulum stress-responsive gene programs through enhancer activation and chromatin looping.
    Jung-Sik Joo, Mikyoung Kim, Sugyung Kim, Hyejin Kim, Hyoung-Pyo Kim.
      Endoplasmic reticulum (ER) stress triggers transcriptional programs that promote either adaptation or apoptosis, yet the epigenetic mechanisms underlying this response remain incompletely understood. Here, integrated multi-omics analyses of unfolded protein response transcription factor knockout cells identify ATF4 as a dominant regulator of ER stress-responsive enhancer activation and chromatin looping. Loss of ATF4 markedly impairs stress-induced H3K27ac accumulation and enhancer-promoter interactions at ATF4-associated regulatory elements, establishing ATF4 as a central organizer of the stress-responsive regulatory landscape. We further identify CHOP as a key functional partner of ATF4 during ER stress. Integrative analyses of ATF4 occupancy and H3K27ac landscapes in CHOP-knockout cells reveal that CHOP selectively modulates ATF4-dependent enhancer activity and controls distinct subsets of stress-responsive genes. This cooperation preferentially promotes apoptosis-associated transcriptional programs while having limited effects on core adaptive responses. Together, our findings define a hierarchical regulatory framework in which ATF4 establishes enhancer activation and chromatin looping networks, whereas CHOP selectively diversifies their output to specify ER stress-responsive gene programs.
    DOI:  https://doi.org/10.1093/nar/gkag641
  3. Nat Commun. 2026 Jun 25.
    Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.
    Zhongkun Liu, Lang Chen, Tong Zhang, Yuliang Wang, Panpan Ma, Xiangwei Zhang, Ronghui Liu, Ruiying Zhang, Xuanhao Zhang, Qingqing Su, Jinyan Huang, Da Wang, Qi Zhang, Cunqi Ye, Yun-Hua Liu.
      Lipid accumulation is a hallmark of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment, yet effective strategies to reprogram this lipid-rich niche and restore anti-tumor immunity remain limited. Here, we show that diacylglycerol O-acyltransferase 1 (DGAT1) as a tumor-intrinsic metabolic checkpoint that promotes immune evasion. DGAT1 inhibition rewires tumor lipid metabolism by promoting increased fatty acid uptake and redistribution, thereby depleting extracellular free fatty acids that impair CD8⁺ T cell function. Mechanistically, decreased palmitate availability alleviates endoplasmic reticulum stress, preserves FOXO1 activity, and supports stem-like CD8⁺ T cell differentiation. This competitive lipid remodeling enhances memory potential, restrains terminal exhaustion, and sensitizes PDAC tumors to PD-1 checkpoint blockade in vivo. Together, our findings identify tumor-immune lipid crosstalk as a key barrier to effective immunity in PDAC and establish DGAT1 as a promising therapeutic target to restore T cell function and improve immunotherapy response.
    DOI:  https://doi.org/10.1038/s41467-026-74315-2
  4. bioRxiv. 2026 Jun 12. pii: 2026.06.11.731694. [Epub ahead of print]
    Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.
    Andrea L Cote, Claire L McIntyre, Joshua A Acklin, Lillian R Delacruz, Yunping Qiu, Irwin J Kurland, Alison E Ringel.
      Cytokine production is a core function of effector T cells, yet the mechanisms that regulate cytokine output during an immune response remain incompletely understood. Here, we identify citrate compartmentalization as a cellular mechanism by which CD8 + T cells couple cytokine production to glucose availability. Under glucose-replete conditions, citrate transport from the mitochondria to the cytosol by the citrate carrier SLC25A1 suppresses calcium-dependent transcription factor activity in effector T cells. Either reducing glucose availability or blocking the exchange of citrate across the mitochondrial membrane raises free cytosolic calcium, thereby driving nuclear localization of Nuclear Factor of Activated T cells (NFAT)-family transcription factors and sustaining cytokine production. As a calcium-chelating metabolite, we show that citrate buffers free cytosolic calcium, thereby linking calcium-dependent signaling to mitochondrial fuel oxidation. We also identify signatures of this regulatory mechanism across hundreds of human cancer cell lines, where there are negative associations between citrate-derived metabolites and calcium-dependent transcriptional programs, and within the spatial organization of human tumors. These findings identify cytosolic citrate as a broadly conserved metabolic rheostat coupling glucose availability to calcium signaling. By adding calcium signaling to the known functions regulated by SLC25A1, our work reveals a mechanism by which mitochondria adaptively tune cytokine expression and other calcium-dependent programs in response to local metabolic conditions, such as nutrients that are available within a tissue or tumor.
    DOI:  https://doi.org/10.64898/2026.06.11.731694
  5. Cell Death Dis. 2026 Jun 23.
    Beyond a waste product: lactate as a master metabolite dictating anti-tumor T-cell fate.
    Xiangyu Dai, Jingjia Chang, Siyue Wang, Lutterodt Bentum-Ennin, Jian Zhou, Xiaomin Zuo, Wanglai Hu.
      Lactate, a key byproduct of tumor metabolic reprogramming, accumulates in the tumor microenvironment (TME) and profoundly shapes T cell-mediated anti-tumor immunity. As research into TME metabolism advances, lactate has emerged as a critical regulator with broad effects on immune function. In many cancers-including gastric cancer, hepatocellular carcinoma, lung cancer, melanoma, and pancreatic cancer-lactate suppresses or remodels anti-tumor immunity by acting on CD8⁺ T cells, regulatory T cells (Tregs), dendritic cells (DCs), and immune checkpoint molecules. The underlying mechanisms are becoming increasingly well-defined. However, major knowledge gaps remain, especially regarding how lactate-associated enzymes (e.g., LDHA), lactate transporters (e.g., MCT4), and signaling pathways impact T cell function. This review summarizes how lactate regulates anti-tumor immune responses and explores emerging immunotherapies targeting lactate metabolism, with a focus on metabolic enzymes and transporters. We cover preclinical and clinical progress on LDHA inhibitors and lactate transporter inhibitors. By comprehensively analyzing lactate's function in the TME, we aim to build a theoretical framework for precision tumor immunotherapy and propose future directions centered on modulating the immune microenvironment through lactate-targeted strategies.
    DOI:  https://doi.org/10.1038/s41419-026-08976-8
  6. J Transl Med. 2026 Jun 23.
    A novel EGR1-driven GLUL/mTOR axis regulates macropinocytosis-mediated crosstalk in pancreatic stellate cell-cancer metastasis.
    Ran Xue, Jun Zhou, Yawei Liu, Yuxi Liu, Jing Wu, Xinran Song.
       BACKGROUND: Pancreatic cancer liver metastasis relies on crosstalk between pancreatic stellate cells (PSCs) and cancer cells, yet the role of transcriptional regulation in this interplay, particularly via macropinocytosis, remains unclear. Here, we aimed to explore a novel EGR1-driven pathway linking PSC function to cancer cell nutrient acquisition and liver metastasis.
    METHODS: Single-cell RNA sequencing (scRNA-seq) was performed on human pancreatic cancer tissues to identify key regulators of PSC-cancer cell crosstalk. ChIP, EMSA, luciferase reporter assays, and western blotting were used to validate transcriptional regulation of GLUL by EGR1. Functional assays included cell proliferation, migration, invasion, and macropinocytosis analyses in co-culture systems. In vivo studies utilized a murine model of pancreatic cancer liver metastasis to assess the impact of the EGR1-GLUL/mTOR axis on metastasis.
    RESULTS: scRNA-seq identified EGR1 as a transcription factor enriched in PSCs, with strong co-expression of GLUL and mTOR pathway genes. EGR1 directly bound the GLUL promoter, promoting its transcription and activating mTOR signaling. This axis suppressed PSC activation (reduced α-SMA expression). EGR1 over-expressed PSCs inhibited pancreatic cancer cell macropinocytosis, leading to impaired nutrient uptake, reduced ATP production, and suppressed malignant behaviors (proliferation, migration, invasion). Additionally, the EGR1-GLUL/mTOR axis reduced liver metastasis in vivo.
    CONCLUSION: The EGR1-driven GLUL/mTOR axis in PSCs suppresses pancreatic cancer progression by inhibiting PSC activation, reducing cancer cell macropinocytosis, and restraining metastasis. This axis represents a promising therapeutic target for disrupting PSC-cancer cell crosstalk in pancreatic cancer.
    Keywords:  Macropinocytosis; Metabolic reprogramming; Metastasis; Pancreatic cancer; Pancreatic stellate cells
    DOI:  https://doi.org/10.1186/s12967-026-08479-2
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