Nature cancerPub Date : 2025-06-01Epub Date: 2025-06-05DOI: 10.1038/s43018-025-00992-5
Kang Qin, Carl M Gay, Lauren A Byers, Jianjun Zhang
{"title":"The current and emerging immunotherapy paradigm in small-cell lung cancer.","authors":"Kang Qin, Carl M Gay, Lauren A Byers, Jianjun Zhang","doi":"10.1038/s43018-025-00992-5","DOIUrl":"10.1038/s43018-025-00992-5","url":null,"abstract":"<p><p>Small-cell lung cancer (SCLC) is a highly aggressive malignancy with poor prognosis. For decades, etoposide-platinum-based chemotherapy had been the mainstay treatment for SCLC; however, despite initial high response rates, most patients developed resistance. In 2019, the US Food and Drug Administration approved the anti-PD-L1 antibody atezolizumab in combination with etoposide-platinum as the new first-line standard of care for extensive-stage SCLC, heralding a paradigm shift in SCLC therapy. This Review aims to provide an overview of the current landscape and emerging treatment strategies of immunotherapies in SCLC as well as highlight the importance of developing biomarkers to facilitate patient selection.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"954-966"},"PeriodicalIF":23.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature cancerPub Date : 2025-06-01Epub Date: 2025-05-09DOI: 10.1038/s43018-025-00966-7
Mansi Saxena, Jonathan F Anker, Julia Kodysh, Timothy O'Donnell, Anna M Kaminska, Marcia Meseck, Olivia Hapanowicz, Scot Anthony Niglio, Andres M Salazar, Hardik R Shah, Yayoi Kinoshita, Rachel Brody, Alex Rubinsteyn, Robert P Sebra, Nina Bhardwaj, Matthew D Galsky
{"title":"Atezolizumab plus personalized neoantigen vaccination in urothelial cancer: a phase 1 trial.","authors":"Mansi Saxena, Jonathan F Anker, Julia Kodysh, Timothy O'Donnell, Anna M Kaminska, Marcia Meseck, Olivia Hapanowicz, Scot Anthony Niglio, Andres M Salazar, Hardik R Shah, Yayoi Kinoshita, Rachel Brody, Alex Rubinsteyn, Robert P Sebra, Nina Bhardwaj, Matthew D Galsky","doi":"10.1038/s43018-025-00966-7","DOIUrl":"10.1038/s43018-025-00966-7","url":null,"abstract":"<p><p>Features of constrained adaptive immunity and high neoantigen burden have been correlated with response to immune checkpoint inhibitors (ICIs). In an attempt to stimulate antitumor immunity, we evaluated atezolizumab (anti-programmed cell death protein 1 ligand 1) in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer. The primary endpoints were feasibility (as defined by neoantigen identification, peptide synthesis, vaccine production time and vaccine administration) and safety. Secondary endpoints included objective response rate, duration of response and progression-free survival for participants treated in the metastatic setting, time to progression for participants treated in the adjuvant setting, overall survival and vaccine-induced neoantigen-specific T cell immunity. A vaccine was successfully prepared (median 20.3 weeks) for 10 of 12 enrolled participants. All participants initiating treatment completed the priming cycle. The most common treatment-related adverse events were grade 1 injection site reactions, fatigue and fever. At a median follow-up of 39 months, three of four participants treated in the adjuvant setting were free of recurrence and two of five participants treated in the metastatic setting with measurable disease achieved an objective response. All participants demonstrated on-treatment emergence of neoantigen-specific T cell responses. Neoantigen vaccination plus ICI was feasible and safe, meeting its endpoints, and warrants further investigation. ClinicalTrials.gov registration: NCT03359239 .</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"988-999"},"PeriodicalIF":23.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature cancerPub Date : 2025-06-01Epub Date: 2025-05-16DOI: 10.1038/s43018-025-00963-w
Severin Guetter, Courtney König, Huiqin Koerkel-Qu, Aleksandra Markiewicz, Sebastian Scheitler, Marie Katzer, Mark Berneburg, Philipp Renner, Beatrix Cucuruz, Leonhard Guttenberger, Veronika Naimer, Kathrin Weidele, Steffi Treitschke, Christian Werno, Hanna Jaser, Tonia Bargmann, Armin Braun, Florian Weber, Katja Evert, Alexander Rochwarger, Christian M Schürch, Katharina Limm, Peter J Oefner, Reinhard Rachel, Felix Baumann, Jens Warfsmann, Lisa Schmidleithner, Kathrin Guetter, Parvaneh Mohammadi, Anja Ulmer, Sebastian Haferkamp, Christoph A Klein, Melanie Werner-Klein
{"title":"MCSP<sup>+</sup> metastasis founder cells activate immunosuppression early in human melanoma metastatic colonization.","authors":"Severin Guetter, Courtney König, Huiqin Koerkel-Qu, Aleksandra Markiewicz, Sebastian Scheitler, Marie Katzer, Mark Berneburg, Philipp Renner, Beatrix Cucuruz, Leonhard Guttenberger, Veronika Naimer, Kathrin Weidele, Steffi Treitschke, Christian Werno, Hanna Jaser, Tonia Bargmann, Armin Braun, Florian Weber, Katja Evert, Alexander Rochwarger, Christian M Schürch, Katharina Limm, Peter J Oefner, Reinhard Rachel, Felix Baumann, Jens Warfsmann, Lisa Schmidleithner, Kathrin Guetter, Parvaneh Mohammadi, Anja Ulmer, Sebastian Haferkamp, Christoph A Klein, Melanie Werner-Klein","doi":"10.1038/s43018-025-00963-w","DOIUrl":"10.1038/s43018-025-00963-w","url":null,"abstract":"<p><p>To investigate the early, poorly understood events driving metastatic progression, we searched for the earliest detectable disseminated cancer cells (DCCs), also often referred to as disseminated tumor cells (DTCs), in sentinel lymph node (SLN) biopsies of 492 patients with stage I-III melanoma. Using micromanipulator-assisted isolation of rare DCCs, single-cell mRNA and DNA sequencing, codetection by indexing immunofluorescence imaging and survival analysis, we identified melanoma-associated chondroitin sulfate proteoglycan (MCSP)<sup>+</sup> melanoma cells as metastasis founder cells (MFCs). We found that DCCs entering SLNs predominantly exhibited a transitory phenotype that, upon interferon-γ exposure triggered by CD8 T cells, dedifferentiated into a neural-crest-like phenotype. This was accompanied by increased production of small extracellular vesicles (sEVs) carrying the immunomodulatory proteins CD155 and CD276 but rarely programmed cell death protein 1 ligand 1. The sEVs suppressed CD8 T cell proliferation and function, facilitating colony formation. Targeting MCSP<sup>+</sup> MFCs or their immune escape mechanisms could be key to curing melanoma early by preventing manifestation of metastasis.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"1017-1034"},"PeriodicalIF":23.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature cancerPub Date : 2025-06-01DOI: 10.1038/s43018-025-01013-1
Luca Danelli
{"title":"Anti-tumor CD8<sup>+</sup> T cell responses are compromised in sickle cell disease.","authors":"Luca Danelli","doi":"10.1038/s43018-025-01013-1","DOIUrl":"10.1038/s43018-025-01013-1","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"909"},"PeriodicalIF":23.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature cancerPub Date : 2025-06-01Epub Date: 2025-04-16DOI: 10.1038/s43018-025-00948-9
Rafael Blanco-Domínguez, Leandro Barros, Mariana Carreira, Manon van der Ploeg, Carolina Condeço, Gabriel Marsères, Cristina Ferreira, Carla Costa, Carlos M Ferreira, Julie Déchanet-Merville, Noel F C C de Miranda, Sofia Mensurado, Bruno Silva-Santos
{"title":"Dual modulation of cytotoxic and checkpoint receptors tunes the efficacy of adoptive Delta One T cell therapy against colorectal cancer.","authors":"Rafael Blanco-Domínguez, Leandro Barros, Mariana Carreira, Manon van der Ploeg, Carolina Condeço, Gabriel Marsères, Cristina Ferreira, Carla Costa, Carlos M Ferreira, Julie Déchanet-Merville, Noel F C C de Miranda, Sofia Mensurado, Bruno Silva-Santos","doi":"10.1038/s43018-025-00948-9","DOIUrl":"10.1038/s43018-025-00948-9","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a challenge for current immunotherapies. Vδ1<sup>+</sup> γδ T cells offer a promising alternative because of their HLA-I-independent cytotoxicity and natural tissue tropism. We developed Delta One T (DOT) cells, a Vδ1<sup>+</sup> γδ T cell-based adoptive cell therapy clinically explored for hematological malignancies but not yet for solid tumors. Here we demonstrate the capacity of DOT cells to target CRC cell lines and patient-derived specimens and organoids in vitro and to control tumor growth in an orthotopic xenograft model of CRC. Notwithstanding, we found tumor-infiltrating DOT cells to exhibit a dysregulated balance of cytotoxic and inhibitory receptors that paralleled that of endogenous Vδ1<sup>+</sup> tumor-infiltrating lymphocytes and limited their cytotoxicity. To maximize efficacy, we unveil two strategies, increasing targeting through upregulation of NKG2D ligands upon butyrate administration and blocking the checkpoints TIGIT and PD1, which synergistically unleashed DOT cell cytotoxicity. These findings support DOT cell-based combinatorial approaches for CRC treatment.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"1056-1072"},"PeriodicalIF":23.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature cancerPub Date : 2025-06-01Epub Date: 2025-06-13DOI: 10.1038/s43018-025-00986-3
Konstantinos Aliazis, Anthos Christofides, Rushil Shah, Yao Yu Yeo, Sizun Jiang, Alain Charest, Vassiliki A Boussiotis
{"title":"The tumor microenvironment's role in the response to immune checkpoint blockade.","authors":"Konstantinos Aliazis, Anthos Christofides, Rushil Shah, Yao Yu Yeo, Sizun Jiang, Alain Charest, Vassiliki A Boussiotis","doi":"10.1038/s43018-025-00986-3","DOIUrl":"10.1038/s43018-025-00986-3","url":null,"abstract":"<p><p>Beyond cancer cells, the tumor microenvironment (TME) includes cells of the innate and adaptive immune systems but also non-immune cells, such as fibroblasts and endothelial cells. Depending on the cues they receive, infiltrating myeloid cells, such as monocytes, macrophages, dendritic cells and neutrophils, perform immune stimulatory or suppressive functions by educating adaptive immune cells, thereby guiding their responses to cancer cells and cancer treatment, such as immune checkpoint blockade (ICB). The increasing understanding that anti-tumor immunity goes beyond T cells with improved functionality, and the unraveling of resistance mechanisms beyond T cell exhaustion, have renewed interest in non-T cell components of the TME to identify novel therapeutic targets and improve ICB responses. Here, we review immune and non-immune cellular components of the TME that regulate adaptive cell responses and their role in ICB response and resistance.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"924-937"},"PeriodicalIF":23.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature cancerPub Date : 2025-06-01Epub Date: 2025-05-26DOI: 10.1038/s43018-025-00964-9
Alexander Beck, Lisa Gabler-Pamer, Gustavo Alencastro Veiga Cruzeiro, Sander Lambo, Bernhard Englinger, McKenzie L Shaw, Olivia A Hack, Ilon Liu, Rebecca D Haase, Carlos A O de Biagi, Alicia Baumgartner, Andrezza Do Nascimento Silva, Marbod Klenner, Pia S Freidel, Jochen Herms, Louisa von Baumgarten, Joerg C Tonn, Niklas Thon, Katharina Bruckner, Sibylle Madlener, Lisa Mayr, Daniel Senfter, Andreas Peyrl, Irene Slavc, Daniela Lötsch, Christian Dorfer, Rene Geyregger, Nicole Amberg, Christine Haberler, Norman Mack, Benjamin Schwalm, Stefan M Pfister, Andrey Korshunov, Lissa C Baird, Edward Yang, Susan N Chi, Sanda Alexandrescu, Johannes Gojo, Marcel Kool, Volker Hovestadt, Mariella G Filbin
{"title":"Cellular hierarchies of embryonal tumors with multilayered rosettes are shaped by oncogenic microRNAs and receptor-ligand interactions.","authors":"Alexander Beck, Lisa Gabler-Pamer, Gustavo Alencastro Veiga Cruzeiro, Sander Lambo, Bernhard Englinger, McKenzie L Shaw, Olivia A Hack, Ilon Liu, Rebecca D Haase, Carlos A O de Biagi, Alicia Baumgartner, Andrezza Do Nascimento Silva, Marbod Klenner, Pia S Freidel, Jochen Herms, Louisa von Baumgarten, Joerg C Tonn, Niklas Thon, Katharina Bruckner, Sibylle Madlener, Lisa Mayr, Daniel Senfter, Andreas Peyrl, Irene Slavc, Daniela Lötsch, Christian Dorfer, Rene Geyregger, Nicole Amberg, Christine Haberler, Norman Mack, Benjamin Schwalm, Stefan M Pfister, Andrey Korshunov, Lissa C Baird, Edward Yang, Susan N Chi, Sanda Alexandrescu, Johannes Gojo, Marcel Kool, Volker Hovestadt, Mariella G Filbin","doi":"10.1038/s43018-025-00964-9","DOIUrl":"10.1038/s43018-025-00964-9","url":null,"abstract":"<p><p>Embryonal tumor with multilayered rosettes (ETMR) is a pediatric brain tumor with dismal prognosis. Characteristic alterations of the chromosome 19 microRNA cluster (C19MC) are observed in most ETMR; however, the ramifications of C19MC activation and the complex cellular architecture of ETMR remain understudied. Here we analyze 11 ETMR samples from patients using single-cell transcriptomics and multiplexed spatial imaging. We reveal a spatially distinct cellular hierarchy that spans highly proliferative neural stem-like cells and more differentiated neuron-like cells. C19MC is predominantly expressed in stem-like cells and controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA binding. Systematic analysis of receptor-ligand interactions between malignant cell types reveals fibroblast growth factor receptor and Notch signaling as oncogenic pathways that can be successfully targeted in preclinical models and in one patient with ETMR. Our study provides fundamental insights into ETMR pathobiology and a powerful rationale for more effective targeted therapies.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"1035-1055"},"PeriodicalIF":23.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature cancerPub Date : 2025-06-01Epub Date: 2025-05-07DOI: 10.1038/s43018-025-00962-x
Julie Bennett, Adrian B Levine, Liana Nobre, Logine Negm, Jiil Chung, Karen Fang, Monique Johnson, Martin Komosa, Stacey Krumholtz, Nuno Miguel Nunes, Mansuba Rana, Scott Ryall, Javal Sheth, Robert Siddaway, Tejus A Bale, Eric Bouffet, Michael D Cusimano, Sunit Das, Jay Detsky, Peter Dirks, Matthias A Karajannis, Paul Kongkham, Alexandra Giantini-Larsen, Bryan Kincheon Li, Mary Jane Lim-Fat, Andrew L Lin, Warren P Mason, Alexandra Miller, James R Perry, Arjun Sahgal, Sameer Farouk Sait, Derek S Tsang, Gelareh Zadeh, Normand Laperriere, Lananh Nguyen, Andrew Gao, Julia Keith, David G Munoz, Uri Tabori, Cynthia Hawkins
{"title":"A population-based analysis of the molecular landscape of glioma in adolescents and young adults reveals insights into gliomagenesis.","authors":"Julie Bennett, Adrian B Levine, Liana Nobre, Logine Negm, Jiil Chung, Karen Fang, Monique Johnson, Martin Komosa, Stacey Krumholtz, Nuno Miguel Nunes, Mansuba Rana, Scott Ryall, Javal Sheth, Robert Siddaway, Tejus A Bale, Eric Bouffet, Michael D Cusimano, Sunit Das, Jay Detsky, Peter Dirks, Matthias A Karajannis, Paul Kongkham, Alexandra Giantini-Larsen, Bryan Kincheon Li, Mary Jane Lim-Fat, Andrew L Lin, Warren P Mason, Alexandra Miller, James R Perry, Arjun Sahgal, Sameer Farouk Sait, Derek S Tsang, Gelareh Zadeh, Normand Laperriere, Lananh Nguyen, Andrew Gao, Julia Keith, David G Munoz, Uri Tabori, Cynthia Hawkins","doi":"10.1038/s43018-025-00962-x","DOIUrl":"10.1038/s43018-025-00962-x","url":null,"abstract":"<p><p>Gliomas are a major cause of cancer-related deaths in adolescents and young adults (AYAs; ages 15-39 years). Different molecular alterations drive gliomas in children and adults, leading to distinct biology and clinical consequences, but the implications of pediatric- versus adult-type alterations in AYAs are unknown. Our population-based analysis of 1,456 clinically and molecularly characterized gliomas in patients aged 0-39 years addresses this gap. Pediatric-type alterations were found in 31% of AYA gliomas and conferred superior outcomes compared to adult-type alterations. AYA low-grade gliomas with specific RAS-MAPK alterations exhibited senescence, tended to arise in different locations and were associated with superior outcomes compared to gliomas in children, suggesting different cellular origins. Hemispheric IDH-mutant, BRAF p.V600E and FGFR-altered gliomas were associated with the risk of malignant transformation, having worse outcomes with increased age. These insights into gliomagenesis may provide a rationale for earlier intervention for certain tumors to disrupt the typical behavior, leading to improved outcomes.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"1102-1119"},"PeriodicalIF":23.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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