While previous studies have reported an increase in future fire weather under global warming scenarios, there is still a limited understanding on how it may evolve under mitigation scenarios. Using idealized emission-driven climate simulations, this analysis examines changes in the extreme fire weather conditions under net-zero emission (ZeroE) and net-negative emission (NegE) scenarios. Compared to peak CO2 levels, the NegE scenario achieves substantially greater fire danger mitigation, particularly in climatologically high-fire-danger regions, because of lower temperatures and increased relative humidity. In contrast, the ZeroE scenario leaves fire danger elevated globally, especially in Northern low-latitude regions. Regional responses are shaped by differences in atmospheric moisture supply, influenced by changes in the strength of the Atlantic meridional overturning circulation and the latitudinal position of the intertropical convergence zone. These findings highlight the crucial role of aggressive CO2 removal strategies in mitigating fire weather dangers and underscore the limitations of ZeroEs alone in addressing global wildfire challenges.
{"title":"Responses of extreme fire weather to CO2 emission reductions and underlying mechanisms.","authors":"Yujin Kim,Seung-Ki Min,Soon-Il An,Seungmok Paik,Sanjit Kumar Mondal","doi":"10.1126/sciadv.adw4705","DOIUrl":"https://doi.org/10.1126/sciadv.adw4705","url":null,"abstract":"While previous studies have reported an increase in future fire weather under global warming scenarios, there is still a limited understanding on how it may evolve under mitigation scenarios. Using idealized emission-driven climate simulations, this analysis examines changes in the extreme fire weather conditions under net-zero emission (ZeroE) and net-negative emission (NegE) scenarios. Compared to peak CO2 levels, the NegE scenario achieves substantially greater fire danger mitigation, particularly in climatologically high-fire-danger regions, because of lower temperatures and increased relative humidity. In contrast, the ZeroE scenario leaves fire danger elevated globally, especially in Northern low-latitude regions. Regional responses are shaped by differences in atmospheric moisture supply, influenced by changes in the strength of the Atlantic meridional overturning circulation and the latitudinal position of the intertropical convergence zone. These findings highlight the crucial role of aggressive CO2 removal strategies in mitigating fire weather dangers and underscore the limitations of ZeroEs alone in addressing global wildfire challenges.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"18 1","pages":"eadw4705"},"PeriodicalIF":13.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937704","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}
Modern edge devices, such as cameras, drones, and internet-of-things nodes, rely on machine learning to enable a wide range of intelligent applications. However, deploying machine learning models directly on the often resource-constrained edge devices demands substantial memory footprints and computational power for real-time inference using traditional digital computing architectures. In this paper, we present WISE, computing architecture for wireless edge networks with two key innovations: disaggregated model access via over-the-air wireless broadcasting for simultaneous inference on multiple edge devices, and in-physics computation of general complex-valued matrix-vector multiplications directly at radio frequency driven by a single frequency mixer. Using a software-defined radio platform, WISE achieves 95.7% image classification accuracy (97.2% audio classification accuracy) with ultralow energy consumption of 6.0 fJ/MAC (2.8 fJ/MAC), which is more than 10× improvement compared to traditional digital computing, e.g., on modern GPUs.
{"title":"Disaggregated machine learning via in-physics computing at radio frequency","authors":"Zhihui Gao, Sri Krishna Vadlamani, Kfir Sulimany, Dirk Englund, Tingjun Chen","doi":"10.1126/sciadv.adz0817","DOIUrl":"https://doi.org/10.1126/sciadv.adz0817","url":null,"abstract":"Modern edge devices, such as cameras, drones, and internet-of-things nodes, rely on machine learning to enable a wide range of intelligent applications. However, deploying machine learning models directly on the often resource-constrained edge devices demands substantial memory footprints and computational power for real-time inference using traditional digital computing architectures. In this paper, we present WISE, computing architecture for wireless edge networks with two key innovations: disaggregated model access via over-the-air wireless broadcasting for simultaneous inference on multiple edge devices, and in-physics computation of general complex-valued matrix-vector multiplications directly at radio frequency driven by a single frequency mixer. Using a software-defined radio platform, WISE achieves 95.7% image classification accuracy (97.2% audio classification accuracy) with ultralow energy consumption of 6.0 fJ/MAC (2.8 fJ/MAC), which is more than 10× improvement compared to traditional digital computing, e.g., on modern GPUs.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"21 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937992","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}
Fan Wang, Dinesh Kumar Behera, Bratin Sengupta, David Li, Miao Yu
Supported ionic liquid membranes (SILMs) stand attractive for gas separation considering the tunability, high gas selectivity, and ease of fabrication. However, the intrinsic instability of SILMs limited their practical use. Here, we designed, fabricated, and investigated an ultrapermeable, ultraselective, and stable nanoconfined ionic liquid (NCIL) membrane for highly efficient CO2 capture. Specifically, the combination of a thin, open, and uniform nanoconfined network of single-walled carbon nanotube with highly CO2–selective ionic liquid carrier enabled the superior CO2 permeance of 1654 GPU and CO2/N2 selectivity of 1132, surpassing most state-of-the-art facilitated transport membranes. The scale-up potential of the NCIL membrane was demonstrated under simulated natural gas flue gas conditions, achieving CO2 enrichment from 4.2 to 98% in a single step. Given the processability and scalability of NCIL membrane, this work affirms the industrial potential of SILMs and offers a viable strategy for designing and fabricating stable SILMs for gas separation.
考虑到可调性、高气体选择性和易于制造，负载离子液体膜（SILMs）对气体分离具有吸引力。然而，其固有的不稳定性限制了其实际应用。在这里，我们设计、制造和研究了一种超渗透、超选择性和稳定的纳米限制离子液体（NCIL）膜，用于高效的CO 2捕获。具体来说，单壁碳纳米管的薄、开放、均匀的纳米限制网络与高CO 2选择性离子液体载体的结合，使CO 2的透过率达到1654 GPU， CO 2 /N 2的选择性达到1132，超过了大多数最先进的促进运输膜。在模拟天然气烟气条件下，NCIL膜的放大潜力得到了验证，在一个步骤中实现了从4.2到98%的CO 2富集。鉴于NCIL膜的可加工性和可扩展性，本研究肯定了silm的工业潜力，并为设计和制造用于气体分离的稳定silm提供了可行的策略。
{"title":"Scalable nanoconfined ionic liquid membranes with ultrapermeance and ultraselectivity for efficient CO2 capture","authors":"Fan Wang, Dinesh Kumar Behera, Bratin Sengupta, David Li, Miao Yu","doi":"10.1126/sciadv.aea1329","DOIUrl":"10.1126/sciadv.aea1329","url":null,"abstract":"<div >Supported ionic liquid membranes (SILMs) stand attractive for gas separation considering the tunability, high gas selectivity, and ease of fabrication. However, the intrinsic instability of SILMs limited their practical use. Here, we designed, fabricated, and investigated an ultrapermeable, ultraselective, and stable nanoconfined ionic liquid (NCIL) membrane for highly efficient CO<sub>2</sub> capture. Specifically, the combination of a thin, open, and uniform nanoconfined network of single-walled carbon nanotube with highly CO<sub>2</sub>–selective ionic liquid carrier enabled the superior CO<sub>2</sub> permeance of 1654 GPU and CO<sub>2</sub>/N<sub>2</sub> selectivity of 1132, surpassing most state-of-the-art facilitated transport membranes. The scale-up potential of the NCIL membrane was demonstrated under simulated natural gas flue gas conditions, achieving CO<sub>2</sub> enrichment from 4.2 to 98% in a single step. Given the processability and scalability of NCIL membrane, this work affirms the industrial potential of SILMs and offers a viable strategy for designing and fabricating stable SILMs for gas separation.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908242","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}
Existing bioelectronics often exhibit megapascal-scale moduli, despite the mechanosensitive nature of cardiomyocytes. Bridging the mechanical mismatch between tissue and bioelectronics is indispensable for building physiologically relevant in vitro cardiac models and advancing therapies. Here, we present Pliable Ultrathin Layered Sensing Electronics (PULSE), a platform with tissue-matched modulus (~10 kilopascals) and stretchable gold microcircuitry for long-term, high-fidelity monitoring of cardiac electrophysiology in vitro. Composed of a soft gel matrix and an ultrathin nanofilm embedded with gold circuits, our device achieves unprecedented tissue integration and preserves natural cardiomyocyte mechanics, resulting in a 140% increase in mechanical contraction and a 100% increase in electrical signals compared to conventional electronics. Cardiac tissue that grows our device exhibited enhanced drug sensitivity and response in cardiac dysfunction, revolutionizing disease modeling. By facilitating seamless interaction at the tissue-electronic interface, our platform offers a transformative perspective for advancing cardiac modeling and next-generation bioelectronic applications.
{"title":"Ultrapliable bioelectronic interface for mechanosensitive cardiac electrophysiology","authors":"Jing Yu, Zhi Jiang, Matthew Ackers-Johnson, Guijin Zou, Feilong Zhang, Ming Zhu, Can Cao, Jiaofu Li, Prasanna Vidyasekar, Wenlong Li, Jianwu Wang, Nuan Chen, Pingqiang Cai, Changtai Guo, Jintong Ai, Yulin Zhou, Srinivas Sheshagiri Prabhu, Huajian Gao, Xiaodong Chen","doi":"10.1126/sciadv.adz1253","DOIUrl":"10.1126/sciadv.adz1253","url":null,"abstract":"<div >Existing bioelectronics often exhibit megapascal-scale moduli, despite the mechanosensitive nature of cardiomyocytes. Bridging the mechanical mismatch between tissue and bioelectronics is indispensable for building physiologically relevant in vitro cardiac models and advancing therapies. Here, we present Pliable Ultrathin Layered Sensing Electronics (PULSE), a platform with tissue-matched modulus (~10 kilopascals) and stretchable gold microcircuitry for long-term, high-fidelity monitoring of cardiac electrophysiology in vitro. Composed of a soft gel matrix and an ultrathin nanofilm embedded with gold circuits, our device achieves unprecedented tissue integration and preserves natural cardiomyocyte mechanics, resulting in a 140% increase in mechanical contraction and a 100% increase in electrical signals compared to conventional electronics. Cardiac tissue that grows our device exhibited enhanced drug sensitivity and response in cardiac dysfunction, revolutionizing disease modeling. By facilitating seamless interaction at the tissue-electronic interface, our platform offers a transformative perspective for advancing cardiac modeling and next-generation bioelectronic applications.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908249","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}
Guillaume Dera, Elise Nardin, Laurent Risser, Marius Albino, Quentin Garnier, Marion Kardacz, Léa Monge-Waleryszak
The Earth’s biosphere exhibits a notable diversity of forms, yet the full morphological extent and limits of life remain largely unexplored. Here, we develop a geometric complexity space for comparing all known unicellular and multicellular phyla using fractal descriptors of the density and heterogeneity of body mass and structure. By applying this approach to a large set of extant biological shapes, we show that life exploits a tiny portion of structural possibilities, clustering around linear, rounded, and densely structured forms, while consistently avoiding complex heteromorphic ones. We show that this restriction results from deep physical, metabolic, and developmental limitations, shaped over geological time by the evolution of body size and ecological lifestyle. Our findings provide a global, quantitative perspective on the long-standing interplay between chance and necessity in evolution, with implications for the expected forms of life beyond Earth.
{"title":"Mapping life’s disparity and evolutionary constraints in a geometric complexity space","authors":"Guillaume Dera, Elise Nardin, Laurent Risser, Marius Albino, Quentin Garnier, Marion Kardacz, Léa Monge-Waleryszak","doi":"10.1126/sciadv.aea6945","DOIUrl":"10.1126/sciadv.aea6945","url":null,"abstract":"<div >The Earth’s biosphere exhibits a notable diversity of forms, yet the full morphological extent and limits of life remain largely unexplored. Here, we develop a geometric complexity space for comparing all known unicellular and multicellular phyla using fractal descriptors of the density and heterogeneity of body mass and structure. By applying this approach to a large set of extant biological shapes, we show that life exploits a tiny portion of structural possibilities, clustering around linear, rounded, and densely structured forms, while consistently avoiding complex heteromorphic ones. We show that this restriction results from deep physical, metabolic, and developmental limitations, shaped over geological time by the evolution of body size and ecological lifestyle. Our findings provide a global, quantitative perspective on the long-standing interplay between chance and necessity in evolution, with implications for the expected forms of life beyond Earth.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908199","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}
Conrad Fallon, Liucong Ling, Brendon H. Cooper, Stefano Ceolin, Tsu-Pei Chiu, Raktim Mitra, Bettina Mühling, Vani Srinivasan, Ayse Damla Durmaz, Daniel Veselinovic, Mahek Kothari, Athanasios Panagiotis Fylaktakis, William J. Glassford, Judith F. Kribelbauer-Swietek, Dimitrios K. Papadopoulos, Richard S. Mann, Remo Rohs, Nicolas Gompel
Fine-tuning of gene expression by transcription factors (TFs) is essential for normal development, but how TF binding is converted into precise expression levels is poorly understood. We used a Drosophila enhancer responding to the TF Distal-less (Dll) to investigate this relationship. By combining computational structure analysis and quantifying relative TFBS affinity and enhancer activity, we describe how TF concentration is converted into precise expression across the developing Drosophila wing. We show that, although the regulatory function of the enhancer generally follows the classical Hill equation, several additional terms are needed to describe the effects of affinity, orientation, sequence, and wing region on the maximum achievable expression and position of transcriptional activity in a tissue. We also found that Dll relies on two distinct sets of amino acid–DNA contacts for binding to higher affinity sites, but contacts are more evenly distributed at lower affinities. Our work integrates information at molecular and tissue scales to describe how the modulation of a single TFBS determines the regulatory function of an enhancer in a complex in vivo environment.
{"title":"Quantitative modulation of a spatial enhancer through the biophysical properties of a transcription factor binding site","authors":"Conrad Fallon, Liucong Ling, Brendon H. Cooper, Stefano Ceolin, Tsu-Pei Chiu, Raktim Mitra, Bettina Mühling, Vani Srinivasan, Ayse Damla Durmaz, Daniel Veselinovic, Mahek Kothari, Athanasios Panagiotis Fylaktakis, William J. Glassford, Judith F. Kribelbauer-Swietek, Dimitrios K. Papadopoulos, Richard S. Mann, Remo Rohs, Nicolas Gompel","doi":"10.1126/sciadv.adz5902","DOIUrl":"10.1126/sciadv.adz5902","url":null,"abstract":"<div >Fine-tuning of gene expression by transcription factors (TFs) is essential for normal development, but how TF binding is converted into precise expression levels is poorly understood. We used a <i>Drosophila</i> enhancer responding to the TF Distal-less (Dll) to investigate this relationship. By combining computational structure analysis and quantifying relative TFBS affinity and enhancer activity, we describe how TF concentration is converted into precise expression across the developing <i>Drosophila</i> wing. We show that, although the regulatory function of the enhancer generally follows the classical Hill equation, several additional terms are needed to describe the effects of affinity, orientation, sequence, and wing region on the maximum achievable expression and position of transcriptional activity in a tissue. We also found that Dll relies on two distinct sets of amino acid–DNA contacts for binding to higher affinity sites, but contacts are more evenly distributed at lower affinities. Our work integrates information at molecular and tissue scales to describe how the modulation of a single TFBS determines the regulatory function of an enhancer in a complex in vivo environment.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908203","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}
Poisoned weapons are a hallmark of advanced hunter-gatherer technology. Through targeted microchemical and biomolecular analyses, we identified traces of toxic plant alkaloids on backed microliths from Umhlatuzana Rock Shelter in KwaZulu-Natal, South Africa, excavated from a level dated to 60,000 years ago. The alkaloids buphandrine and epibuphanisine only originate from Amaryllidaceae indigenous to southern Africa. The most likely source is Boophone disticha (L.f.) Herb. bulb exudate, also associated with historically documented arrow poisons. To our knowledge, we present the first direct evidence for the application of this plant-based poison on the tips of Pleistocene hunting weapons. The discovery highlights the complexity of subsistence strategies and cognition in southern Africa since the mid-Pleistocene.
{"title":"Direct evidence for poison use on microlithic arrowheads in Southern Africa at 60,000 years ago","authors":"Sven Isaksson, Anders Högberg, Marlize Lombard","doi":"10.1126/sciadv.adz3281","DOIUrl":"10.1126/sciadv.adz3281","url":null,"abstract":"<div >Poisoned weapons are a hallmark of advanced hunter-gatherer technology. Through targeted microchemical and biomolecular analyses, we identified traces of toxic plant alkaloids on backed microliths from Umhlatuzana Rock Shelter in KwaZulu-Natal, South Africa, excavated from a level dated to 60,000 years ago. The alkaloids buphandrine and epibuphanisine only originate from Amaryllidaceae indigenous to southern Africa. The most likely source is <i>Boophone disticha</i> (L.f.) Herb. bulb exudate, also associated with historically documented arrow poisons. To our knowledge, we present the first direct evidence for the application of this plant-based poison on the tips of Pleistocene hunting weapons. The discovery highlights the complexity of subsistence strategies and cognition in southern Africa since the mid-Pleistocene.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908204","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}
Arctic extremes—not only gradual trends—are reshaping ecosystems. Sustained monitoring is vital to detect, understand, and respond to these transformative events.
{"title":"Beyond averages: Why Arctic extremes matter","authors":"Torben R. Christensen","doi":"10.1126/sciadv.aee7980","DOIUrl":"10.1126/sciadv.aee7980","url":null,"abstract":"<div >Arctic extremes—not only gradual trends—are reshaping ecosystems. Sustained monitoring is vital to detect, understand, and respond to these transformative events.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908197","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}
Qi Shang, Chenwei Jiang, Mingmei Guo, Minglu Tang, Jiapei Yang, Junjie Xie, Xiaoran An, Qiang Zhang, Feihu Wang
Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, demonstrates persistent resistance to immunotherapy due to its profoundly immunosuppressive microenvironment and markedly limited T cell infiltration. In this context, we engineered a STING agonist–incorporated prodrug hydrogel that orchestrates dual activation of innate and adaptive immunity to prevent postoperative GBM recurrence. We found that this in situ–forming hydrogel integrates seamlessly with tumor resection procedures, serves as a drug depot for sustained tumoral releases of therapeutic agents, and thus reprograms the tumor microenvironment by promoting M1 macrophage polarization, suppressing regulatory T cell activity, and enhancing cytotoxic T lymphocyte infiltration, thereby establishing a robust antitumor immune response. As a postoperative adjuvant therapy, the hydrogel effectively inhibits orthotopic GBM recurrence and extends animal survival while establishing durable immune memory against tumor rechallenge. Our findings demonstrate the translational potential of immunologically engineered hydrogels for STING-activated immunotherapy in preventing postresection GBM recurrence.
{"title":"STING stimulation via supramolecular prodrug hydrogel boosts innate-adaptive immune cross-talk to prevent glioblastoma recurrence","authors":"Qi Shang, Chenwei Jiang, Mingmei Guo, Minglu Tang, Jiapei Yang, Junjie Xie, Xiaoran An, Qiang Zhang, Feihu Wang","doi":"10.1126/sciadv.adx9671","DOIUrl":"10.1126/sciadv.adx9671","url":null,"abstract":"<div >Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, demonstrates persistent resistance to immunotherapy due to its profoundly immunosuppressive microenvironment and markedly limited T cell infiltration. In this context, we engineered a STING agonist–incorporated prodrug hydrogel that orchestrates dual activation of innate and adaptive immunity to prevent postoperative GBM recurrence. We found that this in situ–forming hydrogel integrates seamlessly with tumor resection procedures, serves as a drug depot for sustained tumoral releases of therapeutic agents, and thus reprograms the tumor microenvironment by promoting M1 macrophage polarization, suppressing regulatory T cell activity, and enhancing cytotoxic T lymphocyte infiltration, thereby establishing a robust antitumor immune response. As a postoperative adjuvant therapy, the hydrogel effectively inhibits orthotopic GBM recurrence and extends animal survival while establishing durable immune memory against tumor rechallenge. Our findings demonstrate the translational potential of immunologically engineered hydrogels for STING-activated immunotherapy in preventing postresection GBM recurrence.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908201","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}
Akhilesh Mishra, Ajay Kumar Sharma, Kuldeep Gupta, Dhanush S. Banka, Burles A. Johnson, Jean Hoffman-Censits, Peng Huang, David J. McConkey, Sridhar Nimmagadda
Optimizing dosing strategies is critical to balance effectiveness and toxicity, especially for drugs with narrow therapeutic windows such as antibody-drug conjugates (ADCs). This study evaluates whether positron emission tomography (PET) imaging targeting Nectin-4 can noninvasively quantify the real-time interaction of the ADC enfortumab vedotin (EV) with tumors in urothelial carcinoma. Using the imaging agent [68Ga]AJ647, dynamic changes in the interaction of EV with Nectin-4 were measured across preclinical models and correlated with therapeutic responses. PET imaging identified dose-dependent variations in Nectin-4 engagement, with suboptimal EV doses resulting in incomplete Nectin-4 engagement and increased tumor growth. Crucially, PET-measured target engagement predicted therapeutic outcomes more reliably than either drug dose or baseline target expression. By defining effective target engagement levels needed for optimal therapeutic outcomes, PET imaging provides a clear benchmark for dosing decisions, maximizing efficacy while potentially reducing exposure to higher, toxic doses and thereby enhancing patient safety.
{"title":"Nectin-4 PET for predicting enfortumab vedotin dose-response in urothelial carcinoma","authors":"Akhilesh Mishra, Ajay Kumar Sharma, Kuldeep Gupta, Dhanush S. Banka, Burles A. Johnson, Jean Hoffman-Censits, Peng Huang, David J. McConkey, Sridhar Nimmagadda","doi":"10.1126/sciadv.ady1111","DOIUrl":"10.1126/sciadv.ady1111","url":null,"abstract":"<div >Optimizing dosing strategies is critical to balance effectiveness and toxicity, especially for drugs with narrow therapeutic windows such as antibody-drug conjugates (ADCs). This study evaluates whether positron emission tomography (PET) imaging targeting Nectin-4 can noninvasively quantify the real-time interaction of the ADC enfortumab vedotin (EV) with tumors in urothelial carcinoma. Using the imaging agent [<sup>68</sup>Ga]AJ647, dynamic changes in the interaction of EV with Nectin-4 were measured across preclinical models and correlated with therapeutic responses. PET imaging identified dose-dependent variations in Nectin-4 engagement, with suboptimal EV doses resulting in incomplete Nectin-4 engagement and increased tumor growth. Crucially, PET-measured target engagement predicted therapeutic outcomes more reliably than either drug dose or baseline target expression. By defining effective target engagement levels needed for optimal therapeutic outcomes, PET imaging provides a clear benchmark for dosing decisions, maximizing efficacy while potentially reducing exposure to higher, toxic doses and thereby enhancing patient safety.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908196","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：