Maria Francesca Allega, Ruhi Deshmukh, Theresa Hillinger, Alena Akhmetshina, Anaïs Oudin, Robert Bielik, Dmitry Soloviev, Victor H. Villar, Tobias Ackermann, Guillaume Bourmeau, Sandeep K. Chahal, Katrina H. Stevenson, Colin Nixon, Robin Shaw, Gillian M. Morrison, Anthony J. Chalmers, Steven M. Pollard, Morten Lund-Johansen, Rolf Bjerkvig, Giorgio Seano, Simone P. Niclou, Einar O. Vik-Mo, David Y. Lewis, David Sumpton, Saverio Tardito
Steroid anti-inflammatory drugs, such as dexamethasone, are routinely used to manage brain tumor–associated edema, yet their impact on brain tumor metabolism remains understudied. Here, a metabolomic screen in naïve glioblastoma cells treated with dexamethasone revealed the accumulation of N1-methylnicotinamide, a nicotinamide N-methyltransferase (NNMT) product, through glucocorticoid receptor activation. Using stable isotope-assisted metabolomics in patients with glioblastoma, we showed that nicotinamide conversion into N1-methylnicotinamide exceeds that into NAD+, leading to a ~7-fold accumulation of N1-methylnicotinamide in tumor compared to surrounding brain tissue. In orthotopic models, NNMT activity was enhanced by dexamethasone selectively in glioblastoma tumors but not in contralateral brain. Leveraging the tumor-specific activity of NNMT, we developed a novel 11C-nicotinamide–based positron emission tomography (PET) approach to visualizing glioblastoma tumors. Furthermore, our findings demonstrate that the dexamethasone-induced methionine-dependent nicotinamide methylation becomes detrimental for glioblastoma when combined with a methionine-restricted diet. These results show that steroids rewire methionine and nicotinamide metabolism, enabling the development of innovative PET imaging and metabolic therapies for glioblastoma.
{"title":"Steroid-dependent metabolic rewiring reveals novel therapeutic and imaging approaches for glioblastoma","authors":"Maria Francesca Allega, Ruhi Deshmukh, Theresa Hillinger, Alena Akhmetshina, Anaïs Oudin, Robert Bielik, Dmitry Soloviev, Victor H. Villar, Tobias Ackermann, Guillaume Bourmeau, Sandeep K. Chahal, Katrina H. Stevenson, Colin Nixon, Robin Shaw, Gillian M. Morrison, Anthony J. Chalmers, Steven M. Pollard, Morten Lund-Johansen, Rolf Bjerkvig, Giorgio Seano, Simone P. Niclou, Einar O. Vik-Mo, David Y. Lewis, David Sumpton, Saverio Tardito","doi":"10.1126/sciadv.adx6539","DOIUrl":"10.1126/sciadv.adx6539","url":null,"abstract":"<div >Steroid anti-inflammatory drugs, such as dexamethasone, are routinely used to manage brain tumor–associated edema, yet their impact on brain tumor metabolism remains understudied. Here, a metabolomic screen in naïve glioblastoma cells treated with dexamethasone revealed the accumulation of <i>N</i><sup>1</sup>-methylnicotinamide, a nicotinamide <i>N</i>-methyltransferase (NNMT) product, through glucocorticoid receptor activation. Using stable isotope-assisted metabolomics in patients with glioblastoma, we showed that nicotinamide conversion into <i>N</i><sup>1</sup>-methylnicotinamide exceeds that into NAD<sup>+</sup>, leading to a ~7-fold accumulation of <i>N</i><sup>1</sup>-methylnicotinamide in tumor compared to surrounding brain tissue. In orthotopic models, NNMT activity was enhanced by dexamethasone selectively in glioblastoma tumors but not in contralateral brain. Leveraging the tumor-specific activity of NNMT, we developed a novel <sup>11</sup>C-nicotinamide–based positron emission tomography (PET) approach to visualizing glioblastoma tumors. Furthermore, our findings demonstrate that the dexamethasone-induced methionine-dependent nicotinamide methylation becomes detrimental for glioblastoma when combined with a methionine-restricted diet. These results show that steroids rewire methionine and nicotinamide metabolism, enabling the development of innovative PET imaging and metabolic therapies for glioblastoma.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 4","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yun Bai, Xuebo Yuan, Yang Weng, Kaiping Yin, Heling Wang, Xiaoyue Ni
Spatial patterning of material phases underpins the functional diversity of natural and engineered composites. However, phase architectures are typically fixed once formed, limiting adaptability. Here, we introduce a digital composite with reprogrammable solid-liquid phase architectures at voxel resolution. Each elastomeric voxel contains a liquid metal composite capable of electrically switching between nonvolatile solid and liquid states within seconds, analogous to rewriting data on a hard disk. High-throughput experiments and coupled modeling demonstrate precise tuning of viscoelastic and plastic properties, as well as programmable constitutive behaviors and strain distributions. A modular assembly strategy allows scalable 3D construction of reprogrammable composites into free-form, bulk geometries. By encoding phase states as digital inputs, the composite unlocks unprecedented access to real-time, voxel-level tuning of material properties.
{"title":"Digital composites with reprogrammable phase architectures","authors":"Yun Bai, Xuebo Yuan, Yang Weng, Kaiping Yin, Heling Wang, Xiaoyue Ni","doi":"10.1126/sciadv.aed9698","DOIUrl":"10.1126/sciadv.aed9698","url":null,"abstract":"<div >Spatial patterning of material phases underpins the functional diversity of natural and engineered composites. However, phase architectures are typically fixed once formed, limiting adaptability. Here, we introduce a digital composite with reprogrammable solid-liquid phase architectures at voxel resolution. Each elastomeric voxel contains a liquid metal composite capable of electrically switching between nonvolatile solid and liquid states within seconds, analogous to rewriting data on a hard disk. High-throughput experiments and coupled modeling demonstrate precise tuning of viscoelastic and plastic properties, as well as programmable constitutive behaviors and strain distributions. A modular assembly strategy allows scalable 3D construction of reprogrammable composites into free-form, bulk geometries. By encoding phase states as digital inputs, the composite unlocks unprecedented access to real-time, voxel-level tuning of material properties.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 4","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Virus-induced inflammation and programmed cell death (PCD) are critical antiviral defenses, prompting viruses like respiratory syncytial virus (RSV) to develop PCD regulation mechanisms. Here, we demonstrate that RSV orchestrates the temporal and sequential regulation of distinct PCD pathways in human macrophages to optimize replication and dissemination. During early stages of infection, RSV activates the PI3K-Akt pathway to induce cFLIP expression, effectively suppressing TNF-driven extrinsic apoptosis. Simultaneously, viral degradation of ZDHHC9 prevents GSDMD-mediated pyroptosis downstream of NLRP3 activation, thereby sustaining an intracellular environment permissive to viral propagation. In contrast, following the completion of replication, RSV subverts caspase-1 signaling to trigger the intrinsic apoptotic cascade via the Casp-1–BID–APAF1–Casp-9 axis, and subsequently promotes GSDME-mediated secondary pyroptosis. This late-stage PCD reprogramming enables synchronized release of virions and pro-inflammatory cytokines, exacerbating pulmonary pathology. These findings delineate a temporally resolved strategy by which RSV balances early immune evasion with subsequent viral dissemination and immunopathology, and identify discrete stage-specific molecular targets for therapeutic intervention in RSV-induced lung disease.
{"title":"RSV temporally reprograms apoptosis and pyroptosis to balance immune evasion and replication","authors":"Cong Liu, Haiwu Zhou, Jian Li, Yang Meng, Jingyu Wang, Mingbin He, Weiwei Wang, Zhifei Li, Yali Qin, Mingzhou Chen","doi":"10.1126/sciadv.adz2496","DOIUrl":"10.1126/sciadv.adz2496","url":null,"abstract":"<div >Virus-induced inflammation and programmed cell death (PCD) are critical antiviral defenses, prompting viruses like respiratory syncytial virus (RSV) to develop PCD regulation mechanisms. Here, we demonstrate that RSV orchestrates the temporal and sequential regulation of distinct PCD pathways in human macrophages to optimize replication and dissemination. During early stages of infection, RSV activates the PI3K-Akt pathway to induce cFLIP expression, effectively suppressing TNF-driven extrinsic apoptosis. Simultaneously, viral degradation of ZDHHC9 prevents GSDMD-mediated pyroptosis downstream of NLRP3 activation, thereby sustaining an intracellular environment permissive to viral propagation. In contrast, following the completion of replication, RSV subverts caspase-1 signaling to trigger the intrinsic apoptotic cascade via the Casp-1–BID–APAF1–Casp-9 axis, and subsequently promotes GSDME-mediated secondary pyroptosis. This late-stage PCD reprogramming enables synchronized release of virions and pro-inflammatory cytokines, exacerbating pulmonary pathology. These findings delineate a temporally resolved strategy by which RSV balances early immune evasion with subsequent viral dissemination and immunopathology, and identify discrete stage-specific molecular targets for therapeutic intervention in RSV-induced lung disease.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 4","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bone metastasis remains a formidable challenge in oncology due to the interdependent triad of immunosuppression, neuropathic pain, and osteolytic destruction. Current treatments fail to holistically address these pathophysiological axes. Here, we develop a reactive oxygen species (ROS)–responsive liposomal nanoplatform (LipoNCs@pGSDMB) that codelivers a polymeric stimulator of interferon genes (STING) agonist and a gasdermin B (GSDMB) plasmid for dual neuro-immune modulation. Upon tumor-selective activation in metastatic bone niches, this nanotherapy induces STING-driven immune priming and GSDMB-mediated pyroptosis, triggering potent antitumor responses. Crucially, LipoNCs@pGSDMB restore voltage-gated calcium channel (VGCC) expression in tumor cells, a prognostic biomarker identified through multiomics analysis of clinical specimens, thereby blocking calcium-dependent neurosignaling and disrupting prometastatic tumor-nerve cross-talk. In breast cancer bone metastasis models, this approach achieves 94% tumor suppression, complete pain resolution, and efficient bone restoration. By converging oxidation-responsive nanomaterial engineering, immunomodulation, and neural circuit reprogramming, this work establishes a paradigm-shifting neuroimmunotherapy platform that dismantles the self-reinforcing metastasis niche while addressing its debilitating sequelae.
由于免疫抑制、神经性疼痛和溶骨破坏三者相互依存，骨转移在肿瘤学中仍然是一个艰巨的挑战。目前的治疗未能全面解决这些病理生理轴。在这里，我们开发了一种活性氧（ROS）响应的脂质体纳米平台（LipoNCs@pGSDMB），该平台共同递送干扰素基因（STING）激动剂的聚合刺激剂和gasdermin B （GSDMB）质粒，用于双重神经免疫调节。在转移性骨龛的肿瘤选择性激活后，这种纳米疗法诱导sting驱动的免疫启动和gsdmb介导的焦亡，引发有效的抗肿瘤反应。至关重要的是，LipoNCs@pGSDMB恢复肿瘤细胞中的电压门控钙通道（VGCC）表达，这是一种通过临床标本多组学分析确定的预后生物标志物，从而阻断钙依赖性神经信号传导并破坏转移性肿瘤-神经串导。在乳腺癌骨转移模型中，该方法可实现94%的肿瘤抑制，完全缓解疼痛和有效的骨修复。通过融合氧化反应纳米材料工程、免疫调节和神经回路重编程，本研究建立了一个范式转换的神经免疫治疗平台，该平台可以拆除自我强化的转移生态位，同时解决其衰弱的后遗症。
{"title":"Oxidation-activated nanotherapy boosts tumor immunity and disrupts tumor-nerve crosstalk to combat bone metastases and cancer pain","authors":"Zhaowei Zhang, Pengfei Chen, Yufei Zheng, Mobai Li, Lan Zhao, Zezhou Fu, Yujie Zhou, Tingyu Zhang, Xuanrong Sun, Dingcheng Zhu, Youqing Shen, Shunwu Fan, Xin Liu, Jiajia Xiang","doi":"10.1126/sciadv.ady1292","DOIUrl":"10.1126/sciadv.ady1292","url":null,"abstract":"<div >Bone metastasis remains a formidable challenge in oncology due to the interdependent triad of immunosuppression, neuropathic pain, and osteolytic destruction. Current treatments fail to holistically address these pathophysiological axes. Here, we develop a reactive oxygen species (ROS)–responsive liposomal nanoplatform (LipoNCs@pGSDMB) that codelivers a polymeric stimulator of interferon genes (STING) agonist and a gasdermin B (GSDMB) plasmid for dual neuro-immune modulation. Upon tumor-selective activation in metastatic bone niches, this nanotherapy induces STING-driven immune priming and GSDMB-mediated pyroptosis, triggering potent antitumor responses. Crucially, LipoNCs@pGSDMB restore voltage-gated calcium channel (VGCC) expression in tumor cells, a prognostic biomarker identified through multiomics analysis of clinical specimens, thereby blocking calcium-dependent neurosignaling and disrupting prometastatic tumor-nerve cross-talk. In breast cancer bone metastasis models, this approach achieves 94% tumor suppression, complete pain resolution, and efficient bone restoration. By converging oxidation-responsive nanomaterial engineering, immunomodulation, and neural circuit reprogramming, this work establishes a paradigm-shifting neuroimmunotherapy platform that dismantles the self-reinforcing metastasis niche while addressing its debilitating sequelae.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 4","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giorgio Minati, Giovanni Rodari, Emanuele Polino, Francesco Andreoli, Davide Poderini, Rafael Chaves, Gonzalo Carvacho, Fabio Sciarrino
Randomness certification is a foundational and practical aspect of quantum information science, essential for securing quantum communication protocols. Traditionally, these protocols have been implemented and validated with a single entanglement source, as in the paradigmatic Bell scenario. However, advancing these protocols to support more complex configurations involving multiple entanglement sources is key to building robust architectures and realizing large-scale quantum networks. Here, we show how to certify randomness in an entanglement-teleportation experiment, the building block of a quantum repeater displaying two independent sources of entanglement. Using the scalar extension method, we address the challenge posed by the nonconvexity of the correlation set, providing effective bounds on an eavesdropper’s knowledge of the shared secret bits. Our theoretical model characterizes the certifiable randomness within the network and is validated through the analysis of experimental data from a photonic quantum network.
{"title":"Randomness certification in a quantum network with independent sources","authors":"Giorgio Minati, Giovanni Rodari, Emanuele Polino, Francesco Andreoli, Davide Poderini, Rafael Chaves, Gonzalo Carvacho, Fabio Sciarrino","doi":"10.1126/sciadv.aea8571","DOIUrl":"10.1126/sciadv.aea8571","url":null,"abstract":"<div >Randomness certification is a foundational and practical aspect of quantum information science, essential for securing quantum communication protocols. Traditionally, these protocols have been implemented and validated with a single entanglement source, as in the paradigmatic Bell scenario. However, advancing these protocols to support more complex configurations involving multiple entanglement sources is key to building robust architectures and realizing large-scale quantum networks. Here, we show how to certify randomness in an entanglement-teleportation experiment, the building block of a quantum repeater displaying two independent sources of entanglement. Using the scalar extension method, we address the challenge posed by the nonconvexity of the correlation set, providing effective bounds on an eavesdropper’s knowledge of the shared secret bits. Our theoretical model characterizes the certifiable randomness within the network and is validated through the analysis of experimental data from a photonic quantum network.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 4","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The Hawaiian-Emperor chain has exhibited two distinct Loa-Kea magmatic groups over the past 8 million years, but their origin remains debated. Using paleographically constrained global mantle convection models, we reproduce the present-day location of the Hawaiian hot spot and the associated spatiotemporal geochemical evolution. The composition of the plume conduit shows conventional concentric zoning prior to the Hawaiian-Emperor Bend and gradually evolves to a north-south bilateral zoning pattern afterward, corresponding to the subparallel Loa-Kea trends. Further analysis suggests that the plume originates from ridges of large low-velocity province (LLVP) induced by the push of slabs. Upwelling at the intersections of ridges is more energetic than at the middle of the ridge, causing bottom-up splitting of plume conduit in the lower mantle that propagates upward, forming bilateral zoning and eventually two independent plumes. This process suggests that bilateral zoning is transient and more common in the Pacific than Africa due to the circum-Pacific subduction.
{"title":"Bilateral Loa-Kea trends of the Hawaiian Islands caused by the bottom-up splitting of plume conduit","authors":"Jie Zhang, Jiashun Hu, Kai Wang","doi":"10.1126/sciadv.adx4095","DOIUrl":"10.1126/sciadv.adx4095","url":null,"abstract":"<div >The Hawaiian-Emperor chain has exhibited two distinct Loa-Kea magmatic groups over the past 8 million years, but their origin remains debated. Using paleographically constrained global mantle convection models, we reproduce the present-day location of the Hawaiian hot spot and the associated spatiotemporal geochemical evolution. The composition of the plume conduit shows conventional concentric zoning prior to the Hawaiian-Emperor Bend and gradually evolves to a north-south bilateral zoning pattern afterward, corresponding to the subparallel Loa-Kea trends. Further analysis suggests that the plume originates from ridges of large low-velocity province (LLVP) induced by the push of slabs. Upwelling at the intersections of ridges is more energetic than at the middle of the ridge, causing bottom-up splitting of plume conduit in the lower mantle that propagates upward, forming bilateral zoning and eventually two independent plumes. This process suggests that bilateral zoning is transient and more common in the Pacific than Africa due to the circum-Pacific subduction.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 4","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yannan Tian, Qingrong Li, Shirin Fatma, Junyi Jiang, Hong Jin, Fuxing Zeng, Raven H. Huang
In bacteria, mRNAs degradation and ribotoxin-induced RNA damage are two main events that lead to the stalling of protein translation. The ubiquitous trans-translation system and several alternative rescue factors rescue the stalled ribosomes caused by truncated mRNAs lacking the stop codons. On the other hand, protein release factor homolog (PrfH) is the only known factor to rescue the stalled ribosome damaged by ribotoxins. Here, we show that a subfamily of PrfH, exemplified by PrfH from Capnocytophaga gingivalis (CgPrfH), rescues both types of stalled ribosomes. Biochemical assays demonstrate that CgPrfH hydrolyzes the peptides attached to P-site transfer RNAs when in complex with both the damaged and intact ribosomes. Cryo-EM structures revealed that CgPrfH uses distinct regions to recognize two stalled ribosomes to orient the GGQ motif for peptide hydrolysis. Thus, using a combination of bioinformatic, biochemical, and structural characterization, we have uncovered a family of ribosome rescue factors that have dual activities to resolve two distinct stalled protein translation events in bacteria.
{"title":"Molecular and structural basis of a subfamily of PrfH rescuing both the damaged and intact ribosomes stalled in translation","authors":"Yannan Tian, Qingrong Li, Shirin Fatma, Junyi Jiang, Hong Jin, Fuxing Zeng, Raven H. Huang","doi":"10.1126/sciadv.aea7378","DOIUrl":"10.1126/sciadv.aea7378","url":null,"abstract":"<div >In bacteria, mRNAs degradation and ribotoxin-induced RNA damage are two main events that lead to the stalling of protein translation. The ubiquitous trans-translation system and several alternative rescue factors rescue the stalled ribosomes caused by truncated mRNAs lacking the stop codons. On the other hand, protein release factor homolog (PrfH) is the only known factor to rescue the stalled ribosome damaged by ribotoxins. Here, we show that a subfamily of PrfH, exemplified by PrfH from <i>Capnocytophaga gingivalis</i> (<i>Cg</i>PrfH), rescues both types of stalled ribosomes. Biochemical assays demonstrate that <i>Cg</i>PrfH hydrolyzes the peptides attached to P-site transfer RNAs when in complex with both the damaged and intact ribosomes. Cryo-EM structures revealed that <i>Cg</i>PrfH uses distinct regions to recognize two stalled ribosomes to orient the GGQ motif for peptide hydrolysis. Thus, using a combination of bioinformatic, biochemical, and structural characterization, we have uncovered a family of ribosome rescue factors that have dual activities to resolve two distinct stalled protein translation events in bacteria.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 4","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David Perea, Alba Gonzalez, Ana Gallego-Cortés, Nerea Sanchez-Gaona, Felix Pumarola, Nuria Ortiz, Ines Llano, Juan Lorente, Vicenç Falcó, Meritxell Genescà, Maria J. Buzon
Natural killer (NK) cells are pivotal effectors in antiviral immunity, yet their tissue-specific roles during acute HIV infection remain poorly defined. Using an ex vivo human tonsillar tissue model, we profile NK cell responses to early HIV infection and uncover distinct subsets with specialized functions. We identify a previously uncharacterized memory-like NK population (CD16+/−CD69+CD49a+CD103+NKG2C+) associated with reduced viral burden and enriched in cytotoxic mediators (GNLY, PRF1, and GZMB), apoptotic ligands (FASLG and TRAIL), cytokine receptors (IL2RA, IL2RB, IL2RG, IL12RB2, and IL18R1) and trafficking molecules (CCL3–5, CCR7, and SELL). Although functionally capable of clearing HIV-infected CD4+ T cells in a tissue-mimetic environment, they show impaired cytotoxicity and transcriptional signs of exhaustion after infection. Conversely, HIV drives the reprogramming of immature CD16−CD69+ NK cells toward a more cytotoxic and migratory effector phenotype. These findings reveal dynamic NK cell adaptations in lymphoid tissue during early HIV infection and highlight tissue-resident NK cells as promising targets for immunotherapeutic intervention.
{"title":"Resident CD49a+CD103+NKG2C+ NK cells restrict HIV infection in human lymphoid tissue explants","authors":"David Perea, Alba Gonzalez, Ana Gallego-Cortés, Nerea Sanchez-Gaona, Felix Pumarola, Nuria Ortiz, Ines Llano, Juan Lorente, Vicenç Falcó, Meritxell Genescà, Maria J. Buzon","doi":"10.1126/sciadv.adz1565","DOIUrl":"10.1126/sciadv.adz1565","url":null,"abstract":"<div >Natural killer (NK) cells are pivotal effectors in antiviral immunity, yet their tissue-specific roles during acute HIV infection remain poorly defined. Using an ex vivo human tonsillar tissue model, we profile NK cell responses to early HIV infection and uncover distinct subsets with specialized functions. We identify a previously uncharacterized memory-like NK population (CD16<sup>+/−</sup>CD69<sup>+</sup>CD49a<sup>+</sup>CD103<sup>+</sup>NKG2C<sup>+</sup>) associated with reduced viral burden and enriched in cytotoxic mediators (GNLY, PRF1, and GZMB), apoptotic ligands (FASLG and TRAIL), cytokine receptors (IL2RA, IL2RB, IL2RG, IL12RB2, and IL18R1) and trafficking molecules (CCL3–5, CCR7, and SELL). Although functionally capable of clearing HIV-infected CD4<sup>+</sup> T cells in a tissue-mimetic environment, they show impaired cytotoxicity and transcriptional signs of exhaustion after infection. Conversely, HIV drives the reprogramming of immature CD16<sup>−</sup>CD69<sup>+</sup> NK cells toward a more cytotoxic and migratory effector phenotype. These findings reveal dynamic NK cell adaptations in lymphoid tissue during early HIV infection and highlight tissue-resident NK cells as promising targets for immunotherapeutic intervention.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 4","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Erratum for the Research Article “TP53 missense–specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer” by L. Urbach et al.","authors":"","doi":"10.1126/sciadv.aef0961","DOIUrl":"10.1126/sciadv.aef0961","url":null,"abstract":"","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 4","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jesse Garcia Castillo, Stephanie Silveria, Leo Schirokauer, Antoine Sauquet, Jessica Hung, Grace Jaworski, Joseph M. Hendricks, Hei Sook Sul, James A. Olzmann, Michel DuPage
A burgeoning approach to treating cancer is the pharmacological induction of ferroptotic cell death of tumor cells. However, the impact of disrupting antiferroptotic pathways in the broader tumor microenvironment (TME), such as in immune cells, is still undefined and may complicate treatments. Here, we show that ferroptosis suppressor protein 1 (FSP1/Aifm2) is critically required for regulatory T cell (Treg cell) resistance to ferroptosis and their immunosuppressive function within the TME. Compared to other canonical ferroptosis regulators such as GPX4 and NRF2, only FSP1 was induced upon T cell activation. Deletion of Aifm2 in all T cells, or Treg cells specifically, enhanced tumor control by selectively disrupting Treg cell immunosuppression within tumors without inciting autoimmune pathology in mice. As opposed to deletion of Gpx4 in all T cells, T cell deletion of Aifm2 did not impair antigen-specific CD8+ T cell responses. These results reveal an opportunity for targeting a regulator of ferroptosis that can not only directly target cancer cells but also simultaneously enhance anticancer immune responses without inciting autoimmunity.
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