Pub Date : 2026-01-16DOI: 10.1016/j.cell.2025.11.038
Marta Puig-Tintó, Sebastian Ortiz, Sasha Meek, Raffaele Coray, Laura I Betancur, Altair C Hernández, Anna Castellet, Eric Kramer, Philipp Hoess, Markus Mund, Andrés Molina-Ribagorda, Mercè Izquierdo-Serra, Baldo Oliva, Alex de Marco, Jonas Ries, Daniel Castaño-Díez, Carlo Manzo, Oriol Gallego
Essential for eukaryotes, multiple copies of the exocyst complex tether each secretory vesicle to the plasma membrane (PM) in constitutive exocytosis. The exocyst higher-order structure (ExHOS) that coordinates the action of these multiple exocysts remains unexplored. We integrated particle tracking, super-resolution microscopy, and cryo-electron tomography to time-resolve the continuum conformational landscape of the ExHOS and to functionally annotate its different conformations. We found that 7 exocysts form a flexible ring-shaped ExHOS that tethers vesicles at <45 nm from the PM. The ExHOS rapidly expands while pulling the vesicle toward the PM in a stepwise mechanism comprising three metastable states at 27, 18, and 5 nm from the PM. After fusion, Sec18 mediates the disassembly of the stationary ExHOS, a function that controls the rate of exocytosis. By resolving biophysical principles in situ, we reconstructed the spatiotemporal dynamics of the multimeric architecture controlling vesicle tethering in exocytosis.
{"title":"Continuum architecture dynamics of vesicle tethering in exocytosis.","authors":"Marta Puig-Tintó, Sebastian Ortiz, Sasha Meek, Raffaele Coray, Laura I Betancur, Altair C Hernández, Anna Castellet, Eric Kramer, Philipp Hoess, Markus Mund, Andrés Molina-Ribagorda, Mercè Izquierdo-Serra, Baldo Oliva, Alex de Marco, Jonas Ries, Daniel Castaño-Díez, Carlo Manzo, Oriol Gallego","doi":"10.1016/j.cell.2025.11.038","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.038","url":null,"abstract":"<p><p>Essential for eukaryotes, multiple copies of the exocyst complex tether each secretory vesicle to the plasma membrane (PM) in constitutive exocytosis. The exocyst higher-order structure (ExHOS) that coordinates the action of these multiple exocysts remains unexplored. We integrated particle tracking, super-resolution microscopy, and cryo-electron tomography to time-resolve the continuum conformational landscape of the ExHOS and to functionally annotate its different conformations. We found that 7 exocysts form a flexible ring-shaped ExHOS that tethers vesicles at <45 nm from the PM. The ExHOS rapidly expands while pulling the vesicle toward the PM in a stepwise mechanism comprising three metastable states at 27, 18, and 5 nm from the PM. After fusion, Sec18 mediates the disassembly of the stationary ExHOS, a function that controls the rate of exocytosis. By resolving biophysical principles in situ, we reconstructed the spatiotemporal dynamics of the multimeric architecture controlling vesicle tethering in exocytosis.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1016/j.cell.2025.12.013
Jason S. Rush, Joshua D. Wertheimer, Steven D. Goldberg, Donald Raymond, Mateusz Szuchnicki, Andrew J. Baltus, Jeff Branson, Christopher F. Stratton, Aaron N. Patrick, Ruth Steele, Suraj Adhikary, Amanda Del Rosario, Annie Liu, Noah J. Gomersall, Michael Chung, Matthew J. Ranaghan, Xiebin Gu, Marta Brandt, Zhifang Cao, Adrian Bebenek, Ramnik J. Xavier
Human genetic association studies highlight key genes involved in disease pathology, yet targets identified by these analyses often fall outside the traditional definitions of druggability. A rare truncated variant of the scaffold protein CARD9 is linked with protection from Crohn’s disease, prompting us to pursue the development of inhibitors that might similarly modulate innate inflammatory responses. Using a phased approach, we first identified a ligandable site on CARD9 using a structurally diverse DNA-encoded library and defined this site in detail through X-ray crystallography. Building upon this, a subsequent ligand displacement screen identified additional molecules that uniquely engage CARD9 and prevent its assembly into scaffolds needed to nucleate a signalosome for downstream nuclear factor κB (NF-κB) induction. These inhibitors suppressed inflammatory cytokine production in dendritic cells and a humanized CARD9 mouse model. Collectively, this study illustrates a strategy for leveraging protective human genetic variants and chemical biology to tackle challenging targets for dampening inflammation.
{"title":"Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity","authors":"Jason S. Rush, Joshua D. Wertheimer, Steven D. Goldberg, Donald Raymond, Mateusz Szuchnicki, Andrew J. Baltus, Jeff Branson, Christopher F. Stratton, Aaron N. Patrick, Ruth Steele, Suraj Adhikary, Amanda Del Rosario, Annie Liu, Noah J. Gomersall, Michael Chung, Matthew J. Ranaghan, Xiebin Gu, Marta Brandt, Zhifang Cao, Adrian Bebenek, Ramnik J. Xavier","doi":"10.1016/j.cell.2025.12.013","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.013","url":null,"abstract":"Human genetic association studies highlight key genes involved in disease pathology, yet targets identified by these analyses often fall outside the traditional definitions of druggability. A rare truncated variant of the scaffold protein CARD9 is linked with protection from Crohn’s disease, prompting us to pursue the development of inhibitors that might similarly modulate innate inflammatory responses. Using a phased approach, we first identified a ligandable site on CARD9 using a structurally diverse DNA-encoded library and defined this site in detail through X-ray crystallography. Building upon this, a subsequent ligand displacement screen identified additional molecules that uniquely engage CARD9 and prevent its assembly into scaffolds needed to nucleate a signalosome for downstream nuclear factor κB (NF-κB) induction. These inhibitors suppressed inflammatory cytokine production in dendritic cells and a humanized CARD9 mouse model. Collectively, this study illustrates a strategy for leveraging protective human genetic variants and chemical biology to tackle challenging targets for dampening inflammation.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"9 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1016/j.cell.2025.12.007
Ji Liu, Tianyu Ma, Rui Yao, Lijuan Li, Qizhen Zheng, Ming Wang
Targeted protein degradation (TPD) has transformed strategies for modulating protein function in both basic biology and therapeutic development. However, current strategies often lack the spatial and temporal precision required for in vivo applications. Herein, we report supramolecular targeting chimeras (SupTACs), a modular and programmable platform that enables tissue-specific and temporally controlled protein degradation in vivo. SupTACs self-assemble into supramolecular nanoparticles (SNPs) that co-localize target-binding ligands and E3 ligase recruiters, thereby facilitating proteasomal degradation through multivalent supramolecular proximity. This strategy achieves robust and tissue-specific degradation, including liver and lung specificity, in multiple species up to non-human primates. As a proof of concept, lung-specific degradation of acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) using SupTACs effectively mitigates ferroptosis and pulmonary inflammation in a murine model of acute lung injury. By integrating modularity, tissue specificity, and temporal regulation, SupTACs establish a versatile platform for precise control of protein degradation for interrogating dynamic signaling networks and developing targeted therapeutics.
靶向蛋白降解（Targeted protein degradation， TPD）已经在基础生物学和治疗发展中改变了调节蛋白质功能的策略。然而，目前的策略往往缺乏在体内应用所需的空间和时间精度。在此，我们报告了超分子靶向嵌合体（SupTACs），这是一个模块化和可编程的平台，可以在体内实现组织特异性和暂时控制的蛋白质降解。suptac自组装成超分子纳米颗粒（snp），其共同定位靶标结合配体和E3连接酶招募者，从而通过多价超分子接近促进蛋白酶体降解。这一策略在包括非人类灵长类动物在内的多种物种中实现了强大的组织特异性降解，包括肝脏和肺特异性。作为概念的证明，在小鼠急性肺损伤模型中，使用SupTACs对酰基辅酶a （CoA）合成酶长链家族成员4 （ACSL4）的肺特异性降解有效地减轻了铁下垂和肺部炎症。通过整合模块化、组织特异性和时间调节，SupTACs建立了一个多功能平台，用于精确控制蛋白质降解，以询问动态信号网络和开发靶向治疗。
{"title":"Multimodal supramolecular targeting chimeras enable spatiotemporally resolved protein degradation in vivo","authors":"Ji Liu, Tianyu Ma, Rui Yao, Lijuan Li, Qizhen Zheng, Ming Wang","doi":"10.1016/j.cell.2025.12.007","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.007","url":null,"abstract":"Targeted protein degradation (TPD) has transformed strategies for modulating protein function in both basic biology and therapeutic development. However, current strategies often lack the spatial and temporal precision required for <em>in vivo</em> applications. Herein, we report supramolecular targeting chimeras (SupTACs), a modular and programmable platform that enables tissue-specific and temporally controlled protein degradation <em>in vivo</em>. SupTACs self-assemble into supramolecular nanoparticles (SNPs) that co-localize target-binding ligands and E3 ligase recruiters, thereby facilitating proteasomal degradation through multivalent supramolecular proximity. This strategy achieves robust and tissue-specific degradation, including liver and lung specificity, in multiple species up to non-human primates. As a proof of concept, lung-specific degradation of acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) using SupTACs effectively mitigates ferroptosis and pulmonary inflammation in a murine model of acute lung injury. By integrating modularity, tissue specificity, and temporal regulation, SupTACs establish a versatile platform for precise control of protein degradation for interrogating dynamic signaling networks and developing targeted therapeutics.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"4 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The rapid accessibility of calvarial immune cells to the brain, in principle, may offer transformative opportunities for overcoming drug delivery barriers in central nervous system (CNS) disorders. Here, we hijacked calvarial immune cells using drug-loaded nanoparticles (NPs) and leveraged their unique migration mechanism through skull-meninges microchannels to bypass the blood-brain barrier (BBB) for CNS drug delivery. We constructed NP-loaded immune cells in situ via intracalvariosseous (ICO) injection, validated their prompt migration in response to CNS perturbation, and targeted therapeutic delivery to CNS lesions. Compared with conventional delivery approaches, this strategy achieved promising therapeutic efficacy in improving both short- and long-term outcomes in preclinical stroke models. Our prospective clinical trial further supports the translational feasibility of ICO immune access in treating malignant stroke. These findings establish skull-based delivery as a promising, clinically translatable route for CNS drug delivery and highlight immune-assisted transport as a potentially transformative strategy for improving therapeutic outcomes in neurological disorders.
{"title":"Nanoparticles hijack calvarial immune cells for CNS drug delivery and stroke therapy","authors":"Xize Gao, Xiangrong Liu, Nanxing Wang, Chengqian Cui, Weiming Liu, Mo Yang, Qin Li, Yunwei Ou, Aiyi Ning, Xinyue Wei, Meiyang Zhang, Shuowen Qiu, Yang Lei, Dongjie Fu, Huimin Li, Leming Sun, Meng Lu, Mingjun Zhang, Yilong Wang","doi":"10.1016/j.cell.2025.12.008","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.008","url":null,"abstract":"The rapid accessibility of calvarial immune cells to the brain, in principle, may offer transformative opportunities for overcoming drug delivery barriers in central nervous system (CNS) disorders. Here, we hijacked calvarial immune cells using drug-loaded nanoparticles (NPs) and leveraged their unique migration mechanism through skull-meninges microchannels to bypass the blood-brain barrier (BBB) for CNS drug delivery. We constructed NP-loaded immune cells <em>in situ</em> via intracalvariosseous (ICO) injection, validated their prompt migration in response to CNS perturbation, and targeted therapeutic delivery to CNS lesions. Compared with conventional delivery approaches, this strategy achieved promising therapeutic efficacy in improving both short- and long-term outcomes in preclinical stroke models. Our prospective clinical trial further supports the translational feasibility of ICO immune access in treating malignant stroke. These findings establish skull-based delivery as a promising, clinically translatable route for CNS drug delivery and highlight immune-assisted transport as a potentially transformative strategy for improving therapeutic outcomes in neurological disorders.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"101 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.cell.2025.12.032
Olivia G. Thomas, Urszula Rykaczewska, Marina Galešić, Rianne T.M. van der Burgt, Nils Hallén, Filippo Ferro, Mattias Bronge, Zoe Marti, Yue Li, Alexandra Hill Riqué, Jianing Lin, Aleksa Krstic, Alicja Gromadzka, András Levente Szonder, Chiara Sorini, María Reina-Campos, Ting Sun, Leslie A. Rubio Rodríguez-Kirby, Özge Dumral, Rasmus Berglund, Majid Pahlevan Kakhki, Milena Z. Adzemovic, Manuel Zeitelhofer, Birce Akpinar, Katarina Tengvall, Ola B. Nilsson, Erik Holmgren, Chiara Starvaggi Cucuzza, Klara Asplund Högelin, Guro Gafvelin, Katharina Fink, Gonçalo Castelo-Branco, Maria Needhamsen, Mohsen Khademi, Fredrik Piehl, Torbjörn Gräslund, Lars Alfredsson, Harald Lund, Per Uhlén, Ingrid Kockum, Roland Martin, Maja Jagodic, Hans Grönlund, André Ortlieb Guerreiro-Cacais, Tomas Olsson
{"title":"Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis","authors":"Olivia G. Thomas, Urszula Rykaczewska, Marina Galešić, Rianne T.M. van der Burgt, Nils Hallén, Filippo Ferro, Mattias Bronge, Zoe Marti, Yue Li, Alexandra Hill Riqué, Jianing Lin, Aleksa Krstic, Alicja Gromadzka, András Levente Szonder, Chiara Sorini, María Reina-Campos, Ting Sun, Leslie A. Rubio Rodríguez-Kirby, Özge Dumral, Rasmus Berglund, Majid Pahlevan Kakhki, Milena Z. Adzemovic, Manuel Zeitelhofer, Birce Akpinar, Katarina Tengvall, Ola B. Nilsson, Erik Holmgren, Chiara Starvaggi Cucuzza, Klara Asplund Högelin, Guro Gafvelin, Katharina Fink, Gonçalo Castelo-Branco, Maria Needhamsen, Mohsen Khademi, Fredrik Piehl, Torbjörn Gräslund, Lars Alfredsson, Harald Lund, Per Uhlén, Ingrid Kockum, Roland Martin, Maja Jagodic, Hans Grönlund, André Ortlieb Guerreiro-Cacais, Tomas Olsson","doi":"10.1016/j.cell.2025.12.032","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.032","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"3 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.cell.2025.12.031
Hyein Kim, Mika Schneider, Yakine Raach, Panajotis Karypidis, Julien Roux, Georgios Perdikaris, Sebastian Holdermann, Laila Kulsvehagen, Anne-Catherine Lecourt, Kerstin Narr, Roman Sankowski, Martin Diebold, Ewelina Bartoszek-Kandler, Josef P. Kapfhammer, Gert Zimmer, Anne-Katrin Pröbstel, Marco Prinz, Ludwig Kappos, Nicholas S.R. Sanderson, Tobias Derfuss
{"title":"Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation","authors":"Hyein Kim, Mika Schneider, Yakine Raach, Panajotis Karypidis, Julien Roux, Georgios Perdikaris, Sebastian Holdermann, Laila Kulsvehagen, Anne-Catherine Lecourt, Kerstin Narr, Roman Sankowski, Martin Diebold, Ewelina Bartoszek-Kandler, Josef P. Kapfhammer, Gert Zimmer, Anne-Katrin Pröbstel, Marco Prinz, Ludwig Kappos, Nicholas S.R. Sanderson, Tobias Derfuss","doi":"10.1016/j.cell.2025.12.031","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.031","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"81 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.cell.2025.12.004
Sébastien Calvignac-Spencer, Carles Lalueza-Fox
Ancient DNA has become a workhorse for evolutionary biologists. In contrast, ancient RNA studies have been rare and often methodologically controversial. Mármol-Sánchez et al. provide compelling evidence that aRNA survived up to ca. 50,000 years in permafrost-preserved mammoth (Mammuthus primigenius) soft tissues. Will this finally pave the way for paleotranscriptomics?
{"title":"A trunkload of ancient RNA","authors":"Sébastien Calvignac-Spencer, Carles Lalueza-Fox","doi":"10.1016/j.cell.2025.12.004","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.004","url":null,"abstract":"Ancient DNA has become a workhorse for evolutionary biologists. In contrast, ancient RNA studies have been rare and often methodologically controversial. Mármol-Sánchez et al. provide compelling evidence that aRNA survived up to ca. 50,000 years in permafrost-preserved mammoth (<em>Mammuthus primigenius</em>) soft tissues. Will this finally pave the way for paleotranscriptomics?","PeriodicalId":9656,"journal":{"name":"Cell","volume":"46 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08Epub Date: 2025-12-15DOI: 10.1016/j.cell.2025.11.020
Yoav Chemla, Orit Itzhaki, Stav Melamed, Chen Weller, Yuval Sade, Paulee Manich, Keren Reshef, Nicolas Xenidis, Avishai Maliah, Gilad Levy, Roma Parikh, Osnat Bartok, Opal Levy, Itay Tal, Gal Aziel, Abraham Nissani, Sharon Yunger, Daniela Likonen, Vitaly Kliminsky, Tamar Golan, Coralie Capron, Valentina Ace, Ronen Levy, Diana Rasoulouniriana, Zohar Eyal, Yuval Barzilay, Roi Balaban, Aseel Khateeb, Rami Khosravi, Amir Grau, Tamar Ziv, Polina Greenberg, Dvir Netanely, Hananya Vaknin, Xunwei Wu, Yael Amitay, Ronen Brenner, Julia María Martínez Gómez, Dov Hershkovitz, Tal Yardeni, Valentina Zemser-Werner, Oren Kobiler, Yael Friedmann, David Bassan, Ron Shamir, Lea Eisenbach, Nadine Santana-Magal, Michael Milyavsky, Galit Eisenberg, Leeat Keren, Merav Cohen, Dvir Gur, Boaz Barak, Michal Lotem, David Sprinzak, Shoshana Greenberger, David Fisher, Michal J Besser, Mehdi Khaled, Pierre Close, Ronnie Shapira, Sebastien Apcher, Asaf Madi, Mitchell P Levesque, Francesca Rapino, Yaron Carmi, Shivang Parikh, Yardena Samuels, Carmit Levy
While melanoma cells often express a high burden of mutated proteins, the infiltration of reactive T cells rarely results in tumor-eradicating immunity. We discovered that large extracellular vesicles, known as melanosomes, secreted by melanoma cells are decorated with major histocompatibility complex (MHC) molecules that stimulate CD8+ T cells through their T cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and T cell receptor sequencing (TCR-seq) analyses revealed that these melanosomes carry MHC-bound tumor-associated antigens with higher affinity and immunogenicity, which compete with their tumor cell of origin for direct TCR-MHC interactions. Analysis of biopsies from melanoma patients confirmed that melanosomes trap infiltrating lymphocytes, induce partial activation, and decrease CD8+ T cell cytotoxicity. Inhibition of melanosome secretion in vivo significantly reduced tumor immune evasion. These findings suggest that MHC export protects melanoma from the cytotoxic effects of T cells. Our study highlights a novel immune evasion mechanism and proposes a therapeutic avenue to enhance tumor immunity.
{"title":"HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion.","authors":"Yoav Chemla, Orit Itzhaki, Stav Melamed, Chen Weller, Yuval Sade, Paulee Manich, Keren Reshef, Nicolas Xenidis, Avishai Maliah, Gilad Levy, Roma Parikh, Osnat Bartok, Opal Levy, Itay Tal, Gal Aziel, Abraham Nissani, Sharon Yunger, Daniela Likonen, Vitaly Kliminsky, Tamar Golan, Coralie Capron, Valentina Ace, Ronen Levy, Diana Rasoulouniriana, Zohar Eyal, Yuval Barzilay, Roi Balaban, Aseel Khateeb, Rami Khosravi, Amir Grau, Tamar Ziv, Polina Greenberg, Dvir Netanely, Hananya Vaknin, Xunwei Wu, Yael Amitay, Ronen Brenner, Julia María Martínez Gómez, Dov Hershkovitz, Tal Yardeni, Valentina Zemser-Werner, Oren Kobiler, Yael Friedmann, David Bassan, Ron Shamir, Lea Eisenbach, Nadine Santana-Magal, Michael Milyavsky, Galit Eisenberg, Leeat Keren, Merav Cohen, Dvir Gur, Boaz Barak, Michal Lotem, David Sprinzak, Shoshana Greenberger, David Fisher, Michal J Besser, Mehdi Khaled, Pierre Close, Ronnie Shapira, Sebastien Apcher, Asaf Madi, Mitchell P Levesque, Francesca Rapino, Yaron Carmi, Shivang Parikh, Yardena Samuels, Carmit Levy","doi":"10.1016/j.cell.2025.11.020","DOIUrl":"10.1016/j.cell.2025.11.020","url":null,"abstract":"<p><p>While melanoma cells often express a high burden of mutated proteins, the infiltration of reactive T cells rarely results in tumor-eradicating immunity. We discovered that large extracellular vesicles, known as melanosomes, secreted by melanoma cells are decorated with major histocompatibility complex (MHC) molecules that stimulate CD8<sup>+</sup> T cells through their T cell receptor (TCR), causing T cell dysfunction and apoptosis. Immunopeptidomic and T cell receptor sequencing (TCR-seq) analyses revealed that these melanosomes carry MHC-bound tumor-associated antigens with higher affinity and immunogenicity, which compete with their tumor cell of origin for direct TCR-MHC interactions. Analysis of biopsies from melanoma patients confirmed that melanosomes trap infiltrating lymphocytes, induce partial activation, and decrease CD8<sup>+</sup> T cell cytotoxicity. Inhibition of melanosome secretion in vivo significantly reduced tumor immune evasion. These findings suggest that MHC export protects melanoma from the cytotoxic effects of T cells. Our study highlights a novel immune evasion mechanism and proposes a therapeutic avenue to enhance tumor immunity.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"233-251.e29"},"PeriodicalIF":42.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.cell.2025.11.035
Chengyu Zou, Peiying Li, Bin Li, Tim Sparwasser, Junying Yuan
Recent advances in regulatory T cell (Treg) biology and clinical application of Treg-based treatments show promise as a new generation of transforming therapeutics for immune-related disorders, positioning Tregs as a “living drug” to rebuild immune tolerance and repair damaged tissues simultaneously. This perspective summarizes the key knowledge on Treg biology and highlights the recent important discoveries in the development of clinical applications based on Treg biology, from low-dose interleukin-2 therapy showing promising results in trials for ALS and adoptive Treg transfer demonstrating efficacy in preventing GVHD to early pilot studies of CAR Tregs. Drawing on these advances, we provide perspectives on key research priorities and translational challenges and set forth a roadmap that integrates basic and clinical insights into developing next-generation therapies focusing on precision tolerance strategies.
{"title":"Next steps in regulatory T cells: Biology and clinical application","authors":"Chengyu Zou, Peiying Li, Bin Li, Tim Sparwasser, Junying Yuan","doi":"10.1016/j.cell.2025.11.035","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.035","url":null,"abstract":"Recent advances in regulatory T cell (Treg) biology and clinical application of Treg-based treatments show promise as a new generation of transforming therapeutics for immune-related disorders, positioning Tregs as a “living drug” to rebuild immune tolerance and repair damaged tissues simultaneously. This perspective summarizes the key knowledge on Treg biology and highlights the recent important discoveries in the development of clinical applications based on Treg biology, from low-dose interleukin-2 therapy showing promising results in trials for ALS and adoptive Treg transfer demonstrating efficacy in preventing GVHD to early pilot studies of CAR Tregs. Drawing on these advances, we provide perspectives on key research priorities and translational challenges and set forth a roadmap that integrates basic and clinical insights into developing next-generation therapies focusing on precision tolerance strategies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"97 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号