Cancer & Metabolism最新文献

{"title":"Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.","authors":"Nneka E Mbah, Damien Sutton, Hanna S Hong, Rashi Singhal, Rosa E Menjivar, Matthew D Perricone, Heather Giza, Peter Sajjakulnukit, Amy L Myers, Zeribe C Nwosu, Jonathan M Alektiar, Jason Lin, Daniel Long, Anthony C Andren, Li Zhang, Howard C Crawford, Timothy L Frankel, Marina Pasca di Magliano, Luigi Franchi, Yatrik M Shah, Costas A Lyssiotis","doi":"10.1186/s40170-026-00428-3","DOIUrl":"10.1186/s40170-026-00428-3","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by profound metabolic rewiring and a strongly immunosuppressive tumor microenvironment, both of which contribute to poor therapeutic responses. Immunogenic cell death (ICD) represents a potential strategy to overcome immune suppression by coupling tumor cell death to anti-tumor immune activation. Here, we investigated whether targeting amino acid metabolism in PDAC can induce ICD and promote tumor immunity. Through a focused metabolic screen in a panel of syngeneic mouse cancer cell lines, we identified cysteine restriction as a robust inducer of multiple damage-associated molecular patterns (DAMPs) in vitro, hallmark features of ICD. In addition to driving DAMPs, cystine-deprived tumor cells also promoted dendritic cell phagocytosis, maturation, and proinflammatory cytokine production in vitro. Because cysteine deprivation is a known trigger of ferroptosis, we further demonstrated that pharmacologic inhibition of glutathione peroxidase 4 (GPX4) similarly elicited ICD-associated features, which were reversible by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). To define additional immune-modulatory signals associated with ferroptosis, we performed metabolomic and lipidomic profiling of cells undergoing, but not yet committed to, ferroptotic death. These analyses revealed selective release of immunosuppressive metabolites and oxidized phospholipids. Consistent with this, conditioned media from ferroptotic cells impaired CD8⁺ T cell proliferation and cytotoxicity in vitro. Thus, together our results indicated that the induction of ferroptotic immunogenic cell death led to the release of both pro- and anti-inflammatory signals. Subsequent analysis in vivo revealed that ferroptotic tumor cells predominantly contributed to a tumor-protective environment. In particular, tumors inoculated with ferroptotic cells were enriched with immunosuppressive myeloid cells and exhibited reduced populations of tumor-infiltrating CD8+ T cells. Further investigation using immune compromised mice suggested that ferroptotic cells may suppress both adaptive and innate immune responses. Collectively, these results underscore the complex and highly context-dependent effects of ferroptosis on tumor immunity, highlighting the critical importance of in vivo models to determine true immunogenic potential within the tumor microenvironment.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13072669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measurement of mitochondria amount and clearance using flow cytometry: effect of mitophagy inhibitors in leukemia cells.","authors":"Tereza Kořánová, Dana Grebeňová, Kateřina Kuželová","doi":"10.1186/s40170-026-00429-2","DOIUrl":"10.1186/s40170-026-00429-2","url":null,"abstract":"<p><p>BACKGROUND: High sensitivity to mitochondria damage belongs to established differences between stem cells of acute myeloid leukemia (AML) and their healthy counterparts. Mitophagy, as the key mitochondria quality control, is a possible therapy target in AML. However, research in this field requires simple and robust methods for functional measurement of mitochondria clearance. METHODS: We developed protocols to analyze (i) the rate of mitochondria clearance and (ii) total mitochondrial mass and mitochondria polarization using MitoTracker dyes and flow cytometry. Substantial improvement was achieved by incorporating (i) a proliferation dye to account for the effect of cell division on mitochondria content and (ii) reference cells to compensate for variable cell density. These protocols were tested in 12 leukemia cell lines with different variants of the tumor suppresor TP53, as well as the adherent cell line HS-5. RESULTS: Repeated analyses confirmed high sensitivity and reproducibility of our protocols. The mitophagy rate in p53-null cells was higher compared to cells with the wild-type p53. Mitophagy inhibition was associated with an increase of the total mitochondria mass. The impact of mitophagy inhibition on mitochondria polarization was context-dependent: mitochondria depolarization was associated with cell death induction whereas hyperpolarization was observed during cell recovery in resistant cell lines. CONCLUSION: Our optimized protocols represent a useful tool for analysis of mitophagy and mitochondria content in various cell types. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13173981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PER2 knockdown drives immunotherapy resistance in gastric cancer via metabolic reprogramming of myeloid-derived suppressor cells.","authors":"Shenggang Zhan, Shixi Lu, Feng Xiong, Haitao Li, Wenbiao Chen","doi":"10.1186/s40170-026-00424-7","DOIUrl":"10.1186/s40170-026-00424-7","url":null,"abstract":"<p><p>Circadian rhythm disruption is increasingly linked to tumor progression and therapy resistance, but its role in immune evasion remains unclear. Here, we demonstrate that knockdown of the core circadian gene PER2 (PER2-KD) drives resistance to immune checkpoint inhibitors (ICIs) in gastric cancer (GC) by promoting monocytic myeloid-derived suppressor cell (M-MDSC) accumulation and metabolic reprogramming. RNA-seq and scRNA-seq revealed that PER2-KD upregulates immunosuppressive genes (e.g., PD-L1, IL-10) while suppressing T cell activation signals. Mechanistically, PER2-KD GC cells secrete elevated VEGF and IL-6, inducing STAT3 phosphorylation in M-MDSCs and enhancing their immunosuppressive function. Untargeted metabolomics identified glycolysis and fatty acid metabolism as key pathways dysregulated in PER2-KD M-MDSCs, with lactate accumulation further amplifying CD8 + T cell dysfunction. In vivo, PER2-KD tumors exhibited accelerated growth, reduced PD-1 blockade efficacy, and shorter survival, accompanied by increased M-MDSC infiltration and lactate levels. Neutralizing VEGF/IL-6 or inhibiting lactate metabolism restored CD8+ T cell activity, suggesting actionable therapeutic targets. Our study unveils PER2-KD as a novel regulator of metabolic-immune crosstalk in GC, providing a mechanistic basis for ICI resistance and highlighting circadian-metabolic interventions to improve immunotherapy outcomes.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13170026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging untargeted metabolomics in combination with machine learning to uncover novel insights into bladder cancer.","authors":"Abu Hena Mostafa Kamal, Vasanta Putluri, Tanmay Gandhi, Chandra Shekar R Ambati, Chandra Sekhar Amara, Karthik Reddy Kami Reddy, Meredith Lauren Spradlin, Amrit Koirala, Sachin B Jorvekar, Sandra L Grimm, Dexue Fu, Krishna Parsawar, Felice de Jong, Chris Beecher, Subrata Sen, Seth P Lerner, M Minhaj Siddiqui, Yair Lotan, Livia S Eberlin, Arun Sreekumar, Cristian Coarfa, Nagireddy Putluri","doi":"10.1186/s40170-026-00427-4","DOIUrl":"10.1186/s40170-026-00427-4","url":null,"abstract":"<p><p>BACKGROUND: Untargeted metabolomics has emerged as a powerful approach to uncover metabolic dysregulation associated with cancer progression. When integrated with a machine learning strategy it facilitates the discovery of key metabolic pathways and predictive biomarkers with high diagnostic and prognostic value. METHODS: In this study, we employed liquid chromatography coupled to high-resolution Tribrid Orbitrap mass spectrometry to perform comprehensive metabolic profiling of bladder cancer (BLCA) as well as predict invasiveness of the disease. RESULTS: By leveraging both in-house retention time-based MS/MS spectral libraries and commercial databases, we robustly identify over 2000 metabolites. In addition, this platform allows identification of novel pathways highlighting metabolic vulnerabilities in BLCA. The application of machine learning algorithms and advanced computational modeling uncovered metabolic signatures that differentiate BLCA from adjacent normal/benign samples and distinguish muscle-invasive from non-muscle-invasive bladder cancer. Our integrative analytical pipeline addresses key challenges in metabolomics-including high dimensionality, metabolite annotation, and biological variability-through feature selection and predictive modeling. We identify candidate metabolic markers with strong potential for early detection and characterize invasiveness of the disease and identify potential therapeutic target pathways. CONCLUSIONS: This work highlights the power of combining untargeted metabolomics with machine learning to map the metabolic landscape of BLCA and to accelerate the development of precision diagnostics and future therapeutic strategies. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13040883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome-driven constraint-based modelling reveals metabolic targets for ovarian cancer.","authors":"Kate E Meeson, Joanne C McGrail, Jean-Marc Schwartz, Stephen S Taylor","doi":"10.1186/s40170-026-00425-6","DOIUrl":"10.1186/s40170-026-00425-6","url":null,"abstract":"<p><p>Constraint-based modelling (CBM) is a powerful computational approach that reconstructs cellular metabolism by integrating ‘omics data with genome-scale metabolic models (GEMs), enabling in silico hypothesis generation and genetic engineering studies. Advances in high-throughput ‘omics technologies and the complete mapping of the human genome have expanded the application of CBM to human systems. Given that altered metabolism is a hallmark of cancer, this disease represents an ideal context for developing and applying CBM workflows. Despite the presence of well-characterised metabolic signatures and vulnerabilities in ovarian cancer, this tumour type remains under-explored within the CBM field. Meanwhile, the limited efficacy of current therapies and the frequent emergence of chemoresistance underscore the need for novel, mechanism-based approaches to therapeutic discovery. In this study, we constructed ovarian cancer-specific metabolic models using an ‘omics integration algorithm that incorporates transcriptomic data in a way that is directed by experimental proliferation measurements. Simulations identified multiple candidate molecules predicted to influence cancer cell proliferation. Among these, triosephosphate isomerase 1 (TPI1) was selected for experimental validation based on qualitative prioritisation criteria. Notably, model predictions were supported by RNA sequencing and colony-formation assays, implicating TPI1 in ovarian cancer cell survival. Our results provide novel insights into the metabolic dependencies of ovarian cancer and demonstrate an omics-integrated CBM workflow that may be broadly applicable for uncovering therapeutic vulnerabilities in other malignancies.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-intrinsic metabolic pathways essential for tumorigenesis and resistance to anti-PD1 in oncogenic Kras-driven lung adenocarcinoma.","authors":"Karthik Vasan, Zachary R Chalmers, Hyewon Kong, Navdeep S Chandel","doi":"10.1186/s40170-026-00426-5","DOIUrl":"10.1186/s40170-026-00426-5","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) targeting PD-1 has transformed cancer therapy, yet many tumors display primary or acquired resistance. Metabolic interactions within the tumor microenvironment are increasingly recognized as key modulators of anti-tumor immunity. To identify tumor-intrinsic metabolic pathways that contribute to resistance to anti-PD1 therapy, we performed an in vivo CRISPR-based negative selection screen using a metabolism-focused sgRNA library in an oncogenic Kras and p53 loss-driven murine lung adenocarcinoma cell line. The IgG control arm revealed essential metabolic dependencies for in vivo tumor growth, including the TCA cycle, electron transport chain, antioxidant pathways, one carbon metabolism and de novo lipogenesis. Differential analysis of anti-PD1–treated tumors uncovered metabolic genes whose loss sensitized cancer cells to PD-1 blockade, highlighting pathways in antigen presentation, metabolite transport, arachidonic acid metabolism, and peroxisomal function. Secondary subpooled screens across multiple lung cancer cell lines validated the prominence of these pathways. Although Pla2g4a emerged as a top candidate across Kras-driven tumors, genetic deletion of this enzyme individually did not enhance responsiveness to PD-1 therapy. Overall, this work defines metabolic vulnerabilities that contribute to primary tumor growth in vivo, while providing a resource for selecting tumor-intrinsic metabolic targets that need further validation for combination strategies with PD-1 blockade.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13104462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A shift in the cellular redox state redirects aspartate for export under glucose deprivation.","authors":"Barbara Konrad, Gabriele Bluemel, Theresa Haitzmann, Tobias Frech, Anke Vandekeere, Mélanie Planque, Visnja Bubalo, Katharina Schindlmaier, Vanessa Jäger, Michael A Dengler, Sarah Stryeck, Luka Brcic, Jörg Lindenmann, Philipp Stiegler, Doruntina Bresilla, Corina T Madreiter-Sokolowski, Tobias Madl, Thomas O Eichmann, Nikolaus Kneidinger, Sarah-Maria Fendt, Katharina Leithner","doi":"10.1186/s40170-026-00420-x","DOIUrl":"10.1186/s40170-026-00420-x","url":null,"abstract":"<p><p>BACKGROUND: Glucose is an important fuel in cancer cells, however, its availability may be limited in solid tumors. Cell-autonomous, metabolic adaptations of cancer cells and non-malignant cells to glucose deprivation are still incompletely understood. METHODS: Here, we addressed the changes in central carbon metabolism in lung cancer cells and normal lung cells facing glucose limitation using stable isotopic labeling followed by nuclear magnetic resonance spectroscopy and mass spectrometry. RESULTS: Elevated levels and the release of newly synthesized aspartate were among the most prominent changes in low compared to high glucose conditions. The low glucose-induced export of aspartate occurred in different lung cancer cell lines, but also bronchial epithelial cells and cancer-associated fibroblasts. It was accompanied by a reduced use of aspartate in purine synthesis and suppressed by hypoxia. A knockout of the malate-aspartate shuttle (MAS) enzyme mitochondrial aspartate aminotransferase (GOT2) decreased aspartate release. Low glucose conditions diminished reduced nicotinamide adenine dinucleotide (NADH) and restoring NADH reversed aspartate synthesis, suggesting that the distal, NADH-dependent arm of the MAS is compromised under glucose deprivation. CONCLUSIONS: Cells accumulate and release aspartate, a biosynthetic precursor and signaling molecule, under low glucose conditions, largely due to a truncated MAS, as part of their adaptive metabolic response. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12955209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147347470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting FANCD2 to overcome enzalutamide resistance in prostate cancer.","authors":"Wenzhen Shi, Juliang Yang, Yue Xu, Huijie Yang, Junquan Hu, Shang Huang","doi":"10.1186/s40170-026-00419-4","DOIUrl":"10.1186/s40170-026-00419-4","url":null,"abstract":"<p><p>BACKGROUND: Fanconi anemia complementation group D2 (FANCD2) is a key component of DNA damage repair and has emerged as a potential cancer therapy target. Its role in enzalutamide (ENZ) resistance in prostate cancer remains unclear. METHODS: FANCD2 expression was examined in prostate cancer cells. Gain- and loss-of-function experiments were performed to assess ferroptosis, mitochondrial morphology, and cell viability. Nrf2 and GPX4 expression were measured to elucidate antioxidant regulation. Combination therapy using the ferroptosis inducer RSL3 and ENZ was evaluated in vitro and in vivo for antitumor efficacy. RESULTS: FANCD2 was significantly upregulated in prostate cancer and promoted ENZ resistance by inhibiting ferrous iron accumulation and lipid peroxidation, thereby suppressing ferroptosis. Mechanistically, FANCD2 stabilized Nrf2, increasing GPX4 expression and maintaining redox homeostasis. FANCD2 downregulation reduced Nrf2 and GPX4 expression, induced mitochondrial damage, and triggered ferroptosis, enhancing sensitivity to ENZ. Furthermore, combined treatment with RSL3 and ENZ synergistically suppressed cell growth, migration, and tumor progression in vivo. CONCLUSION: FANCD2 regulates ferroptosis through the Nrf2–GPX4 axis, contributing to ENZ resistance in prostate cancer. Targeting FANCD2 or combining enzalutamide with ferroptosis inducers offers a promising strategy to overcome drug resistance and improve therapeutic outcomes. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12997758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting HIF-2α in colorectal cancer reveals a cholesterol biosynthesis-dependent ferroptotic vulnerability.","authors":"Prarthana J Dalal, Rashi Singhal, Boyan Hu, Drew Stark, Nicholas J Rossiter, Chesta Jain, Peter Sajjakulnukit, Costas A Lyssiotis, Yatrik M Shah","doi":"10.1186/s40170-026-00421-w","DOIUrl":"10.1186/s40170-026-00421-w","url":null,"abstract":"<p><p>Colorectal carcinoma (CRC) remains a major cause of cancer-related mortality with rising incidence in individuals under 55, highlighting the need for novel therapeutic strategies. Hypoxia-inducible factor 2 alpha (HIF-2α) has been genetically validated as a critical driver of colorectal tumorigenesis, with intestinal epithelium–specific deletion in mice markedly reducing tumor formation. PT2385, a selective small-molecule HIF-2α inhibitor applied in renal cell carcinoma treatment, has not been evaluated in CRC. Here, we demonstrate that HIF-2α inhibition with PT2385 alone fails to suppress CRC growth in vitro under normoxic or hypoxic conditions and in xenograft models in vivo. To identify vulnerabilities induced by HIF-2α blockade, we performed an unbiased CRISPR metabolic screen. This revealed cholesterol biosynthesis as a critical dependency. Targeting this pathway with clinically approved statins (atorvastatin, pitavastatin, simvastatin) synergized with PT2385 to suppress CRC cell growth, reduce colony formation, and enhance cell death. Genetic knockdown of HIF-2α Mechanistic studies show that combined HIF-2α and HMG-CoA reductase inhibition with statins promotes ferroptosis, characterized by increased lipid peroxidation and depletion of antioxidant metabolites. These effects are fully reversed by the ferroptosis inhibitor liproxstatin-1. In vivo, co-administration of PT2385 and atorvastatin significantly reduced tumor growth and increased ferroptotic cell death in xenografts, confirming the mechanistic link. Collectively, these findings uncover a metabolic vulnerability of CRC to dual HIF-2α and cholesterol biosynthesis inhibition supporting a clinically actionable strategy that leverages safe, FDA-approved statins to potentiate HIF-2α-targeted therapy.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12998000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caspase-1/11 deficiency and cold exposure enhance the anti-tumor activity of brown adipose tissue secretome against breast cancer cells.","authors":"Luís Henrique Corrêa, Heloisa Antoniella Braz-de-Melo, Igor de Oliveira Santos, Sarah Pinho Bezerra, Julia Perin Manchine, Nathalia Cristina Silva Lago, Clarissa Maria Alves Portacio-Santos, Raquel das Neves Almeida, Dalila Juliana Silva Ribeiro, Tiago Medeiros-Furquim, Lívia Pimentel Sant'ana, Matheus Garcia de Fragas, Felipe Teixeira Lopes, Rhanoica Oliveira Guerra, Niels Olsen Saraiva Câmara, Mariana S Castro, Wagner Fontes, Dario Simões Zamboni, Kelly Grace Magalhães","doi":"10.1186/s40170-026-00422-9","DOIUrl":"10.1186/s40170-026-00422-9","url":null,"abstract":"<p><p>BACKGROUND: Adipose tissue metabolic plasticity and inflammation critically influence tumor progression through endocrine signaling. While white adipose tissue (WAT) has been linked to pro-tumorigenic effects in obesity-related cancers, the influence of brown adipose tissue (BAT) and its secretome on breast cancer remains incompletely understood. Furthermore, how caspase-1/11–mediated inflammasome signaling regulates adipose tissue endocrine function in this context is largely unexplored. This study investigated the differential effects of WAT and BAT secretomes on breast cancer aggressiveness and elucidate the impact of caspase-1/11 deficiency on adipose tissue-tumor crosstalk. METHODS: Conditioned media (CM) were generated from WAT and BAT of wild-type (WT) and caspase-1/11 knockout (KO) C57BL/6 mice, including animals subjected to cold-induced BAT activation. 4T1 breast cancer cells were exposed to these secretomes, and carcinogenic parameters were assessed, including viability (MTT), cell death (Annexin-V/PI), proliferation (CFSE), migration (wound healing assay), lipid droplet biogenesis (BODIPY and Oil Red staining and microscopy), oxidative stress (ROS and nitrite quantification), and cytokine production (ELISA). Additionally, splenocytes were also stimulated with the secretomes to assess their effect on T and NKT cell activation (Flow cytometry). Global proteomic profiling (LC-MS/MS) was performed to identify key molecular pathways affected of exposed breast cancer cells compared to controls. Statistical analyses included ANOVA with Tukey’s or Student’s t-test, as appropriate. RESULTS: WAT-CM promoted lipid droplet accumulation in 4T1 cells. In contrast, BAT-CM reduced tumor cell viability, cell proliferation, and migration further triggering oxidative stress and cell death. Immunophenotypic analysis revealed that BAT-CM modulated immune activation. These antitumor effects were amplified by caspase-1/11 deficiency and cold-induced BAT activation. Proteomic analyses revealed distinct modulation of metabolic, inflammatory, and immune-related pathways in WAT- and BAT-CM-treated tumor cells. Histological and cytokine analyses demonstrated that caspase-1/11 deficiency led to reduced adipocyte size, increased BAT macrophage infiltration, and a softened inflammatory profile. CONCLUSIONS: Our findings uncover a novel anti-tumor role for the BAT secretome in breast cancer, modulated by caspase-1/11-dependent inflammasome signaling and cold-induced activation. Targeting adipose tissue plasticity and inflammasome pathways may offer new strategies to reprogram the tumor microenvironment. These results open novel perspectives for exploring BAT-derived factors as metabolic-based therapeutics for breast cancer. </p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":"3"},"PeriodicalIF":5.9,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12918741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}