bims-stacyt 2025-06-15 papers

Front Oncol. 2025 ;15 1568524

Targeting the leptin receptor promotes MDA-MB-231 cells' metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue.

Carol Costa Encarnação, Carolinne Souza Amorim, Victor Aguiar Franco, Luiz Gabriel Xavier Botelho, Ronan Christian Machado Dos Santos, Isadora Ramos-Andrade, Luiz Guilherme Kraemer-Aguiar, Christina Barja-Fidalgo, João Alfredo Moraes, Mariana Renovato-Martins.

Introduction: Leptin, a key adipokine secreted by adipose tissue (AT), has emerged as a critical mediator linking obesity and breast cancer, both of which are major global health concerns. Elevated leptin levels are detected in the circulation and in extracellular vesicles (EVs) released by adipose tissue, particularly in cases of obesity. These leptin-enriched EVs have been implicated in various stages of tumor progression. In this study, we investigated the effects of leptin within extracellular vesicles (EVs) secreted by obese adipose tissue on the functional properties and metabolism of MDA-MB-231 breast cancer cells, a model for triple-negative breast cancer (TNBC).
Method: MDA-MB-231 cells were treated with EVs derived from the subcutaneous adipose tissue of eutrophic (EUT EVs) and obese (OB EVs) individuals.
Results: Our findings revealed that OB EVs induced significant phosphorylation of STAT3, a key signaling molecule in cancer progression, and promoted increased cell migration, dependent on fatty acid oxidation (FAO). This effect was reversed in the presence of a leptin receptor antagonist, highlighting leptin's pivotal role in these processes. Additionally, OB EVs caused metabolic changes, including reduced lactate levels and decreased pyruvate kinase (PK) activity, while increasing glucose-6-phosphate dehydrogenase (G6PDH) activity, suggesting metabolic reprogramming that supports tumor cell survival and proliferation. In addition to metabolic alterations, OB EVs also impacted mitochondrial dynamics. We observed an upregulation of fusion and fission markers and a redistribution of mitochondria toward the cell periphery, which supports migration. Moreover, OB EVs increased the invasive capacity of MDA-MB-231 cells, an effect mediated by matrix metalloproteinase-9 (MMP-9).
Discussion: Overall, our results highlight how obese adipose tissue modulates breast cancer cell behavior, with leptin-enriched EVs playing a central role in driving migration, metabolic reprogramming, and invasiveness, thereby promoting tumor malignancy. This study underscores the importance of EVs in the obesity-cancer link and offers new insights for therapeutic strategies targeting leptin signaling and EV-mediated communication in breast cancer.

Keywords: adipose tissue; breast cancer; extracellular vesicles; leptin; obesity

DOI: https://doi.org/10.3389/fonc.2025.1568524

Cell Chem Biol. 2025 Jun 03. pii: S2451-9456(25)00168-0. [Epub ahead of print]

EGR2 O-GlcNAcylation orchestrates the development of protumoral macrophages to limit CD8+ T cell antitumor responses.

Yuchen Zhang, Hongpeng Li, Yi Hao, Jiaqi Chen, Xing Chen, Hang Yin.

Tumor associated macrophages (TAMs) exhibit a high capacity to take up glucose. However, how metabolic cues derived from glucose rewire TAMs remains unclear. Here, we report that glucose metabolism-driven protein O-GlcNAcylation increases in TAMs and shapes the differentiation and protumoral function of TAMs. Deficiency of O-GlcNAc transferase (OGT) in TAMs restricted tumor growth by reducing the proportion of C1QC+ F4/80+ TREM2+ MerTK+ TAMs as well as Trem2 expression, which in turn preserved the cytotoxic function of effector CD8+ T cells while exhibiting reduced features of exhaustion. Mechanistically, O-GlcNAc targeted the macrophage-specific transcription factor EGR2 to promote its transcriptional activity. Transcriptional profiling revealed that OGT increased EGR2-related motifs accessibility in TAMs. O-GlcNAcylation of EGR2 at serine 299 enhanced its binding to myeloid cell differentiation-associated genes, including Trem2, thus facilitating the protumoral function of TAMs in GM-CSF-sufficient tumor. Overall, our work defines a tumor-specific reprogramming of protumoral TAMs via O-GlcNAc-modified EGR2 transcriptional regulation.

Keywords: CD8(+) T cells; EGR2; GM-CSF; TREM2; anti-tumor immunity; glucose metabolism; post-translational modification; protein O-GlcNAcylation; tumor associated macrophages; tumor microenvironment

DOI: https://doi.org/10.1016/j.chembiol.2025.05.007

Autophagy. 2025 Jun 12.

Tumorous cholesterol biosynthesis curtails anti-tumor immunity by preventing MTOR-TFEB-mediated lysosomal degradation of CD274/PD-L1.

Huina Wang, Xiuli Yi, Di Qu, Xiangxu Wang, Hao Wang, Hengxiang Zhang, Yuqi Yang, Tianwen Gao, Weinan Guo, Chunying Li.

Enhanced cholesterol biosynthesis is a hallmark metabolic characteristic of cancer, exerting an oncogenic role by supplying intermediate metabolites that regulate intracellular signaling pathways. The pharmacological blockade of cholesterol biosynthesis has been well documented as a promising therapeutic approach in cancer. Particularly, cholesterol biosynthesis is linked to macroautophagy/autophagy and lysosome metabolism, with the engagement of the critical autophagy regulators like MTOR to be fully activated by lysosomal cholesterol trafficking and accumulation. Previous studies have primarily focused on the role of cholesterol biosynthesis in tumor cell-intrinsic biological processes, whereas its involvement in tumor immune evasion and the underlying mechanisms related to autophagy or lysosome metabolism remain elusive. Herein, through bioinformatics analysis we discovered a negative correlation between cholesterol biosynthesis and the score of tumor-infiltrating lymphocytes in cancers. Inhibition of tumor cell cholesterol biosynthesis leads to increased infiltration and activation of CD8+ T cells in the tumor microenvironment, which is largely responsible for the impairment of tumor growth. Mechanistically, cholesterol biosynthesis inhibition impairs the activation of MTOR at lysosomes, thereby promoting the nuclear translocation of TFEB and downstream lysosome biosynthesis, facilitating the degradation of CD274/PD-L1 within lysosomes in tumor cells. Ultimately, the HMGCR-MTOR-LAMP1 axis that connects cholesterol, lysosome and tumor immunology, predicts poor response to immunotherapy and worse prognosis of patients with melanoma. These findings unveil an immunomodulatory role of tumorous cholesterol biosynthesis via the regulation of CD274 lysosomal degradation. Targeting cholesterol biosynthesis holds promise as a potential therapeutic strategy in cancer, particularly when combined with immune checkpoint blockade.

Keywords: Cholesterol; PD-L1; TFEB; immune evasion; lysosome; protein degradation

DOI: https://doi.org/10.1080/15548627.2025.2519066

Nutr Diabetes. 2025 Jun 10. 15(1): 26

Interactions among nutrition, metabolism and the immune system in the context of starvation and nutrition-stimulated obesity.

Borros Arneth.

The endogenous intestinal microflora and environmental factors, such as diet, play central roles in immune homeostasis and reactivity. The microflora and diet both influence body weight and insulin resistance, notably through their effects on adipose cells. The aim of this study was to provide an update on how nutrient-derived factors (mostly focusing on fatty acids and glucose) impact the innate and acquired immune systems, including the immune system in the gut and its associated bacterial flora. The main source of fuel for energy-demanding immune cells is glucose. Insulin-responsive adipose tissue and Toll-like receptors (TLRs), which are part of the innate immune system and expressed in immune cells, intestinal cells, and adipocytes, are essential actors in the complex balance that ensures systemic immune and metabolic health. Leptin decreases during weight loss and increases brain activity in regions involved in the cognitive, emotional, and sensory control of food intake; restoring leptin levels maintains weight loss and reverses the alterations in brain activity. Obesity-triggering nutrients affect adipocytes, whereas proinflammatory leptin prompts the generation of cytokines and T cells. Collectively, data on nutrients demonstrate that starvation culminates in fat depletion, which then impacts the immune system. In people with obesity, inflammation originates largely from adipose tissue.

DOI: https://doi.org/10.1038/s41387-025-00383-w

Ageing Res Rev. 2025 Jun 06. pii: S1568-1637(25)00143-6. [Epub ahead of print]110 102797

Long-term fasting and its influence on inflammatory biomarkers: A comprehensive scoping review.

Isabella de Ciutiis, Shadia Djakovic, Maria Lastra Cagigas, Andrius Masedunskas, Lee Smith, Claudio Franceschi, Luigi Fontana.

OBJECTIVES: Despite the rising popularity of prolonged fasting, its biological effects and potential risks remain unclear, with claims suggesting it reduces inflammation. This systematic scoping review examines the impact of prolonged fasting (≥48 h) on key inflammatory biomarkers: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α).
METHODS: Following PRISMA-ScR guidelines, a comprehensive search of PubMed, Medline (Ovid), Web of Science, Embase (Classic and Embase), and Scopus was conducted for studies published up to August 2024. Eligible studies were peer-reviewed human clinical trials that investigated prolonged fasting's effects on inflammatory markers.
RESULTS: Following a systematic search across multiple databases, 14 studies met the inclusion criteria. Contrary to popular belief, the majority of studies reported either no change or an increase in inflammatory biomarkers during prolonged fasting. CRP levels frequently rose-often significantly-during fasting periods, particularly in individuals with overweight or obesity. Some studies also reported increases in TNF-α and IL-6, though results were less consistent. Importantly, several studies showed a reduction or normalization of CRP levels after refeeding, suggesting that the inflammatory response to fasting may be transient or adaptive. These discrepancies may be due to differences in fasting duration, participant characteristics, and study design.
CONCLUSIONS: This review finds limited and inconsistent evidence on prolonged fasting's effects on inflammation, with varied study designs and lack of standard protocols. Overall, prolonged fasting appears to lead to an increase in inflammation that may represent an adaptive mechanism. Future research, particularly randomized controlled trials, is needed to assess the long-term impacts of fasting on inflammation and metabolic diseases across different populations.

Keywords: C-reactive protein; Cytokines; Human studies; Inflammation; Inflammatory markers; Interleukin-6 (IL-6); Prolonged fasting; Scoping review; Tumor necrosis factor-alpha (TNFα)

DOI: https://doi.org/10.1016/j.arr.2025.102797

Acta Pharm Sin B. 2025 May;15(5): 2673-2686

Sulfafurazole dimers potentiate chemo-immunotherapy of low immunogenic breast cancer by preventing the PD-L1 exosomes secretion.

Zheng Wang, Ronghui Yin, Lin Zhang, Shiyu Li, Zhanwei Zhou, Minjie Sun.

The αPD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes secreted in the environment, causing tumor immune evasion. Here, we proposed an exosome biogenesis inhibition strategy to suppress tumor exosomes secretion from the source, reducing the inhibitory effect on T cells and enhancing chemo-immunotherapy efficacy. We developed sulfafurazole homodimers (SAS) with disulfide linkages, effectively releasing the drug in response to glutathione (GSH) and inhibiting 4T1 tumor-derived exosomes secretion. Subsequently, gemcitabine (Gem) was encapsulated to induce immunogenic cell death (ICD). Consequently, Gem@SAS inhibited the secretion of tumor exosomes by more than 70%, increased proliferation and granzyme B secretion ability of T cells by more than 2 times, and showed superior efficacy in breast cancer treatment as well as lung metastasis of breast cancer.

Keywords: Breast cancer; Carrier free nanomedicine; Chemo-immunotherapy; Exosomes depletion; GSH responsive delivery system; Immunogenic cell death; Programmed death ligand 1; T cells exhaustion

DOI: https://doi.org/10.1016/j.apsb.2025.03.007