Cellular and Molecular Life Sciences最新文献

{"title":"The HBV large envelope protein initiates virion assembly by recruiting capsids at membrane rich domains related to late endosome.","authors":"Florian Seigneuret, Sébastien Eymieux, Vanessa Sarabia-Vega, Roxane Lemoine, Julien Burlaud-Gaillard, Pierre Raynal, Christophe Hourioux, Camille Sureau, Philippe Roingeard, Hugues de Rocquigny","doi":"10.1007/s00018-025-05574-3","DOIUrl":"10.1007/s00018-025-05574-3","url":null,"abstract":"<p><p>A crucial step of HBV (Hepatitis B Virus) virion morphogenesis is the envelopment of the nucleocapsid by the viral envelope proteins, which is triggered by an interaction between the HBV core protein and the large HBV envelope protein. To document this protein-protein interaction, we co-expressed core and large HBV envelope (LHBs) in Huh-7 cells and subjected the cells to microscopy examination by Fluorescence Resonance Energy Transfer (FRET) and Transmission Electron Microscopy (TEM). Our results show that the sole expression of the core protein leads to assembly of capsids that remain individually isolated within the whole cell, but particularly within the nucleus. In the presence of LHBs, capsids were observed as large clusters in a membrane rich region peripheral to the nucleus. In this context, core-LHBs complex co-localize with markers of the late endosome/multivesicular bodies, this co-localization being driven by LHBs. These results thus show that LHBs binds to the core proteins when preassembled into capsid, at membranes of the late endosome, where the inner capsid and the outer envelope meet to assemble a virion.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"128"},"PeriodicalIF":6.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotinamide metabolism reprogramming drives reversible senescence of glioblastoma cells.","authors":"Ashwin Narayanan, Mirca S Saurty-Seerunghen, Jessica Michieletto, Virgile Delaunay, Arnaud Bruneel, Thierry Dupré, Chris Ottolenghi, Clément Pontoizeau, Lucrezia Ciccone, Andreas De La Vara, Ahmed Idbaih, Laurent Turchi, Thierry Virolle, Hervé Chneiweiss, Marie-Pierre Junier, Elias A El-Habr","doi":"10.1007/s00018-025-05641-9","DOIUrl":"10.1007/s00018-025-05641-9","url":null,"abstract":"<p><p>Recent studies show that metabolites, beyond their metabolic roles, can induce significant changes in cell behavior. Herein, we investigate the non-canonical role of nicotinamide (vitamin B3) on glioblastoma (GB) cell behavior. Nicotinamide induced senescence in GB cells, characterized by reduced proliferation, chromatin reorganization, increased DNA damage, enhanced beta-galactosidase activity, and decreased Lamin B1 expression. Nicotinamide-induced senescence was accompanied by an unexpected reprogramming of its metabolism, marked by simultaneous downregulated transcription of NNMT (nicotinamide N-methyltransferase) and NAMPT (nicotinamide phosphoribosyl-transferase). Nicotinamide effects on GB cells were mediated by decreased levels of SOX2. Consistently, analyses of patients' single cell transcriptome datasets showed that GB cells with low NNMT and NAMPT expression levels were enriched in gene modules related to senescence. Remarkably, senescent GB cells retained tumor-forming ability in vivo, albeit to a lesser extent compared to control cells. Further experiments at the single-cell level and transcriptomic analyses demonstrated that nicotinamide-induced senescence in GB cells is fully reversible. Overall, our findings identify a novel reversible senescent state in GB tumors and highlight the non-canonical role of nicotinamide as a key driver of cancer cell plasticity.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"126"},"PeriodicalIF":6.2,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11928343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYLD links the TRAF6/sNASP axis to TLR4 signaling in sepsis-induced acute lung injury.","authors":"Yu-Chih Wu, Bing-Hua Su, Wun-Hao Cheng, Cheng-Tai Zou, Edward T H Yeh, Feng-Ming Yang","doi":"10.1007/s00018-025-05654-4","DOIUrl":"10.1007/s00018-025-05654-4","url":null,"abstract":"<p><p>Sepsis-induced acute lung injury (ALI) involves severe lung dysfunction and leads to high morbidity and mortality rates due to the lack of effective treatments. The somatic nuclear autoantigenic sperm protein (sNASP)/tumor necrosis factor receptor-associated factor 6 (TRAF6) axis plays a crucial role in regulating inflammatory responses during sepsis through Toll-like receptor 4 (TLR4) signaling. However, it is unclear whether deubiquitinating enzymes affect the TRAF6/sNASP axis. In this study, we showed that cylindromatosis (CYLD) directly binds to the sNASP and prevents TRAF6 activation. When TLR4 is activated, phosphorylation of sNASP releases CYLD from the TRAF6/sNASP complex, leading to TRAF6 autoubiquitination and the production of proinflammatory cytokines. To stop TRAF6 activation, a complex of sNASP, TRAF6, and CYLD is reformed once dephosphorylation of sNASP occurs by protein phosphatase 4 (PP4). Silencing sNASP negated the inhibitory effects of CYLD on interleukin (IL)-6 and TNF-α production after lipopolysaccharide (LPS) treatment. Similarly, the absence of CYLD also reduced PP4's negatively regulated production of proinflammatory cytokines, indicating that phosphorylation is crucial for the interaction between sNASP and CYLD as well as TRAF6 activation. Finally, mice infected with a recombinant adenovirus carrying the CYLD gene (Ad-CYLD WT), but not a mutation, showed significant reductions in cecal ligation and puncture (CLP)-mediated lung injury and proinflammatory cytokine production. In conclusion, CYLD alleviated sepsis-induced inflammation by interacting with the TRAF6/sNASP axis. These findings suggest that CYLD could be a potential therapeutic target for treating sepsis-induced ALI.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"124"},"PeriodicalIF":6.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"R-spondins secreted by human pancreas-derived mesenchymal stromal cells support pancreatic organoid proliferation.","authors":"Alessandro Cherubini, Clelia Pistoni, Maria Chiara Iachini, Cecilia Mei, Francesco Rusconi, Valeria Peli, Mario Barilani, Dorian Tace, Noemi Elia, Fabio Lepore, Vittoria Caporale, Lorenzo Piemonti, Lorenza Lazzari","doi":"10.1007/s00018-025-05658-0","DOIUrl":"https://doi.org/10.1007/s00018-025-05658-0","url":null,"abstract":"<p><p>Mesenchymal stromal cells (MSC) play a critical role in the stem cell niche, a specialized microenvironment where stem cells reside and interact with surrounding cells and extracellular matrix components. Within the niche, MSC offer structural support, modulate inflammatory response, promote angiogenesis and release specific signaling molecules that influence stem cell behavior, including self-renewal, proliferation and differentiation. In epithelial tissues such as the intestine, stomach and liver, MSC act as an important source of cytokines and growth factors, but not much is known about their role in the pancreas. Our group has established a standardized technology for the generation of pancreatic organoids. Herein, we investigated the role of pancreatic mesenchymal stromal cells in the regulation of human pancreatic organoid proliferation and growth, using this 3D model in a co-culture system. We particularly focused on the capacity of pancreatic MSC to produce R-spondin factors, which are considered critical regulators of epithelial growth. We propose the development of a complex in vitro system that combines organoid technology and mesenchymal stromal cells, thereby promoting the assembloid new research era.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"125"},"PeriodicalIF":6.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen-induced circFAM171A1 regulates sheep myoblast proliferation through the oar-miR-485-5p/MAPK15/MAPK pathway.","authors":"Runqing Chi, Yufang Liu, Peng Wang, Fan Yang, Xiangyu Wang, Xiaoyun He, Ran Di, Mingxing Chu","doi":"10.1007/s00018-025-05639-3","DOIUrl":"10.1007/s00018-025-05639-3","url":null,"abstract":"<p><p>Estrogen is an important hormone that affects muscle development in female animals. Previous studies have shown that estrogen can protect muscle cells from apoptosis by inhibiting the MAPK signaling pathway. However, the molecular mechanisms by which estrogen-induced MAPK signaling regulates myoblast growth and development remain unclear. In this study, RNA-seq was performed on ovariectomized small-tailed Han (OR-STH) sheep and sham surgery small-tailed Han (STH) sheep to analyze the effects of estrogen on muscle growth and development in female animals. There were 8721 differentially expressed circRNAs (DECs), 143 differentially expressed miRNAs (DEMs) and 2238 differentially expressed mRNAs (DEGs) in the longissimus dorsi between the OR-STH and STH groups. Bioinformatics analysis revealed that the differentially expressed gene MAPK15 was significantly enriched in the MAPK signaling pathway, which is important for muscle development. Therefore, we constructed the ceRNA network circFAM171A1/oar-miR-485-5p/MAPK15 and explored its effect on muscle growth and development. The results of the molecular mechanism experiments indicated that circFAM171A1 can sponge oar-miR-485-5p to regulate MAPK15. The addition of the exogenous hormone estradiol (E₂) to sheep myoblasts could induce circFAM171A1, regulate the expression of oar-miR-485-5p and MAPK15, and promote the proliferation of sheep myoblasts. The results showed that MAPK15 and circFAM171A1 significantly promoted the proliferation of myoblasts and inhibited the apoptosis of myoblasts in sheep, whereas oar-miR-485-5p inhibited the expression of MAPK15 and circFAM171A1, inhibited myoblast proliferation and promoted apoptosis. Furthermore, circFAM171A1 attenuated the inhibitory effect of oar-miR-485-5p on myoblasts. In summary, estrogen induced the expression of circFAM171A1 in sheep myoblasts, and circFAM171A1 can act as a sponge for oar-miR-485-5p to promote the expression of the target gene MAPK15 and ultimately regulate the proliferation of sheep myoblasts. This study provides new insights into the molecular mechanism of estrogen regulation of muscle growth and development in female animals.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"123"},"PeriodicalIF":6.2,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of TLRs as signaling cascades to combat infectious diseases: a review.","authors":"Md Salauddin, Debaraj Bhattacharyya, Indranil Samanta, Sukumar Saha, Mengzhou Xue, Md Golzar Hossain, Chunfu Zheng","doi":"10.1007/s00018-025-05631-x","DOIUrl":"10.1007/s00018-025-05631-x","url":null,"abstract":"<p><p>Investigating innate immunity and its signaling transduction is essential to understand inflammation and host defence mechanisms. Toll-like receptors (TLRs), an evolutionarily ancient group of pattern recognition receptors, are crucial for detecting microbial components and initiating immune responses. This review summarizes the mechanisms and outcomes of TLR-mediated signaling, focusing on motifs shared with other immunological pathways, which enhances our understanding of the innate immune system. TLRs recognize molecular patterns in microbial invaders, activate innate immunity and promote antigen-specific adaptive immunity, and each of them triggers unique downstream signaling patterns. Recent advances have highlighted the importance of supramolecular organizing centers (SMOCs) in TLR signaling, ensuring precise cellular responses and pathogen detection. Furthermore, this review illuminates how TLR pathways coordinate metabolism and gene regulation, contributing to adaptive immunity and providing novel insights for next-generation therapeutic strategies. Ongoing studies hold promise for novel treatments against infectious diseases, autoimmune conditions, and cancers.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"122"},"PeriodicalIF":6.2,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esc peptides and derivatives potentiate the activity of CFTR with gating defects and display antipseudomonal activity in cystic fibrosis-like lung disease.","authors":"Loretta Ferrera, Floriana Cappiello, Arianna Venturini, Hexin Lu, Bruno Casciaro, Giacomo Cappella, Giulio Bontempi, Alessandra Corrente, Raffaele Strippoli, Federico Zara, Y Peter Di, Luis J V Galietta, Mattia Mori, Maria Luisa Mangoni","doi":"10.1007/s00018-025-05633-9","DOIUrl":"10.1007/s00018-025-05633-9","url":null,"abstract":"<p><p>Cystic fibrosis (CF) is a rare disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a chloride channel with an important role in the airways. Despite the clinical efficacy of present modulators in restoring the activity of defective CFTR, there are patients who show persistent pulmonary infections, mainly due to Pseudomonas aeruginosa. Recently, we reported an unprecedented property of antimicrobial peptides i.e. Esc peptides, which consists in their ability to act as potentiators of CFTR carrying the most common mutation (the loss of phenylalanine 508) affecting protein folding, trafficking and gating. In this work, by electrophysiology experiments and computational studies, the capability of these peptides and de-novo designed analogs was demonstrated to recover the function of other mutated forms of CFTR which severely affect the channel gating (G551D and G1349D). This is presumably due to direct interaction of the peptides with the nucleotide binding domains (NBDs) of CFTR, followed by a novel local phenomenon consisting in distancing residues located at the cytosolic side of the NBDs interface, thus stabilizing the open conformation of the pore at its cytosolic end. The most promising peptides for the dual antimicrobial and CFTR potentiator activities were also shown to display antipseudomonal activity in conditions mimicking the CF pulmonary ion transport and mucus obstruction, with a higher efficacy than the clinically used colistin. These studies should assist in development of novel drugs for lung pathology in CF, with dual CFTR potentiator and large spectrum antibiotic activities.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"121"},"PeriodicalIF":6.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11920571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What are the ethical limits of claimed scientific authorship? a case report of relevance.","authors":"Juan-Carlos Argüelles","doi":"10.1007/s00018-025-05650-8","DOIUrl":"10.1007/s00018-025-05650-8","url":null,"abstract":"<p><p>Since its discovery in the middle of the XX century, research into autophagy has undergone a spectacular expansion, particularly in the early 1990s. A number of physiological processes involving autophagy have been revealed and important human pathologies have been associated with perturbations in autophagy. In 2008 the \"Guidelines for the use and interpretation of assays for monitoring autophagy\" was launched with the purpose of collecting in a single document all the available information to monitor autophagy, which, it was thought, might be useful for established groups and any new scientists attracted by this field. The usefulness and success of this Guidelines has led to the subsequent publication of editions every 4 years, a task in which a growing number of authors have become involved and consequently included in the list of contributors. However, this worthy initiative and closely associated metric parameters has led to important scholarly repercussions in terms of perceived merits, grants and financial support obtained, professional careers and other areas concerning scientific activity. All these aspects are carefully examined in this contribution.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"120"},"PeriodicalIF":6.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interneuron migration impairment and brain region-specific DNA damage response following irradiation during early neurogenesis in mice.","authors":"Lisa Berden, Nicholas Rajan, André Claude Mbouombouo Mfossa, Isabeau De Bie, Emre Etlioglu, Mohammed Abderrafi Benotmane, Mieke Verslegers, Najat Aourz, Ilse Smolders, Jean-Michel Rigo, Bert Brône, Roel Quintens","doi":"10.1007/s00018-025-05643-7","DOIUrl":"10.1007/s00018-025-05643-7","url":null,"abstract":"<p><p>Embryonic DNA damage resulting from DNA repair deficiencies or exposure to ionizing radiation during early neurogenesis can lead to neurodevelopmental disorders, including microcephaly. This has been linked to an excessive DNA damage response in dorsal neural progenitor cells (NPCs), resulting in p53-dependent apoptosis and premature neuronal differentiation which culminates in depletion of the NPC pool. However, the effect of DNA damage on ventral forebrain NPCs, the origin of interneurons, remains unclear. In this study, we investigated the sequelae of irradiation of mouse fetuses at an early timepoint of forebrain neurogenesis. We focused on the neocortex (NCX) and medial ganglionic eminence (MGE), key regions for developing dorsal and ventral NPCs, respectively. Although both regions showed a typical p53-mediated DNA damage response consisting of cell cycle arrest, DNA repair and apoptosis, NCX cells displayed prolonged cell cycle arrest, while MGE cells exhibited more sustained apoptosis. Moreover, irradiation reduced the migration speed of interneurons in acute living brain slices and MGE explants, the latter indicating a cell-intrinsic component in the defect. RNA sequencing and protein analyses revealed disruptions in actin and microtubule cytoskeletal-related cellular machinery, particularly in MGE cells. Despite massive acute apoptosis and an obvious interneuron migration defect, prenatally irradiated animals did not show increased sensitivity to pentylenetetrazole-induced seizures, nor was there a reduction in cortical interneurons in young adult mice. This suggests a high plasticity of the developing brain to acute insults during early neurogenesis. Overall, our findings indicate that embryonic DNA damage induces region-specific responses, potentially linked to neurodevelopmental disorders.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"118"},"PeriodicalIF":6.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade.","authors":"Felipe I Espinoza, Stoyan Tankov, Sylvie Chliate, Joana Pereira Couto, Eliana Marinari, Thibaud Vermeil, Marc Lecoultre, Nadia El Harane, Valérie Dutoit, Denis Migliorini, Paul R Walker","doi":"10.1007/s00018-025-05642-8","DOIUrl":"10.1007/s00018-025-05642-8","url":null,"abstract":"<p><p>Glioblastoma (GBM) is an aggressive primary brain tumor with dismal clinical prognosis and resistance to current therapies. GBM progression is facilitated by the tumor microenvironment (TME), with an immune infiltrate dominated by tumor-associated microglia/macrophages (TAMs) and regulatory T cells (Tregs). The TME is also characterized by hypoxia and the expression of hypoxia-inducible factors (HIFs), with HIF-2α emerging as a potential regulator of tumor progression. However, its role in GBM immunosuppression remains unknown. Here, we investigate HIF-2α and the use of the HIF-2α inhibitor PT2385 to modulate the TME in the immunocompetent GL261 mouse GBM model. PT2385 administration in vivo decreased tumor volume and prolonged survival of tumor-bearing mice, without affecting GL261 viability in vitro. Notably, HIF-2α inhibition alleviated the immunosuppressive TME and synergized with immune checkpoint blockade (ICB) using αPD-1 and αTIM-3 antibodies to promote long-term survival. Comprehensive analysis of the immune infiltrate through single-cell RNA sequencing and flow cytometry revealed that combining PT2385 with ICB reduced numbers of pro-tumoral macrophages and Tregs while increasing numbers of microglia, with a corresponding transcriptional modulation towards an anti-tumoral profile of these TAMs. In vitro, deletion of HIF-2α in microglia impeded their polarization towards a pro-tumoral M2-like profile, and its inhibition impaired Treg migration. Our results show that targeting HIF-2α can switch an immunosuppressive TME towards one that favors a robust and sustained response to ICB based immunotherapy. These findings establish that clinically relevant HIF-2α inhibitors should be explored not only in malignancies with defects in the HIF-2α axis, but also in those exhibiting an immunosuppressive TME that limits immunotherapy responsiveness.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"119"},"PeriodicalIF":6.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}