Pub Date : 2026-02-03DOI: 10.1158/2159-8290.cd-24-1853
Pietro Berico, Amanda Flores Yanke, Fatemeh Vand-Rajabpour, Catherine Do, Irving Simonin Wilmer, Ines Delclaux, Tara Muijlwijk, Robert Stagnitta, Martha Estefania Vázquez-Cruz, Theodore Sakellaropoulos, Matheus Ribeiro. Costa, Annie Cristhine Moraes Sousa-Squiavinato, Michelle Krogsgaard, Ata S. Moshiri, Iman Osman, Jane A. Skok, Patricia A. Possik, Carla Daniela Robles-Espinoza, Amanda W. Lund, Markus Schober, Eva Hernando
Ultraviolet (UV)-induced DNA mutations generate genetic drivers of cutaneous melanoma and numerous neoantigens that can trigger anti-tumor immunity. Melanoma cells must therefore rapidly evade immune detection by modulating cell-autonomous epigenetic mechanisms and tumor–microenvironment interactions. Although angiogenesis typically facilitates immune infiltration, solid tumors increase vascularization while limiting immune cell entry. By comparing transcription factor (TF) expression across early-stage melanoma, naevi, and other cancers, we found that the homeodomain TF HOXD13 drives a melanoblast-like program upregulated in melanoma and strongly correlated with angiogenesis and immune cell exclusion. Using transcriptomics, 3D chromatin profiling, and in vivo models, we show that HOXD13 promotes tumor growth by enhancing angiogenesis and suppressing T-cell infiltration. HOXD13 orchestrates 3D enhancer–promoter contacts activating VEGFA, SEMA3A, and CD73, which remodel vasculature and elevate immunosuppressive adenosine. Consistently, HOXD13-induced tumor growth is reversed by combined VEGFR and adenosine receptor (AdR) inhibition, revealing a dual pro-angiogenic and immunosuppressive HOXD13 axis with therapeutic relevance.
{"title":"A targetable developmental program co-regulates angiogenesis and immune evasion in melanoma","authors":"Pietro Berico, Amanda Flores Yanke, Fatemeh Vand-Rajabpour, Catherine Do, Irving Simonin Wilmer, Ines Delclaux, Tara Muijlwijk, Robert Stagnitta, Martha Estefania Vázquez-Cruz, Theodore Sakellaropoulos, Matheus Ribeiro. Costa, Annie Cristhine Moraes Sousa-Squiavinato, Michelle Krogsgaard, Ata S. Moshiri, Iman Osman, Jane A. Skok, Patricia A. Possik, Carla Daniela Robles-Espinoza, Amanda W. Lund, Markus Schober, Eva Hernando","doi":"10.1158/2159-8290.cd-24-1853","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1853","url":null,"abstract":"Ultraviolet (UV)-induced DNA mutations generate genetic drivers of cutaneous melanoma and numerous neoantigens that can trigger anti-tumor immunity. Melanoma cells must therefore rapidly evade immune detection by modulating cell-autonomous epigenetic mechanisms and tumor–microenvironment interactions. Although angiogenesis typically facilitates immune infiltration, solid tumors increase vascularization while limiting immune cell entry. By comparing transcription factor (TF) expression across early-stage melanoma, naevi, and other cancers, we found that the homeodomain TF HOXD13 drives a melanoblast-like program upregulated in melanoma and strongly correlated with angiogenesis and immune cell exclusion. Using transcriptomics, 3D chromatin profiling, and in vivo models, we show that HOXD13 promotes tumor growth by enhancing angiogenesis and suppressing T-cell infiltration. HOXD13 orchestrates 3D enhancer–promoter contacts activating VEGFA, SEMA3A, and CD73, which remodel vasculature and elevate immunosuppressive adenosine. Consistently, HOXD13-induced tumor growth is reversed by combined VEGFR and adenosine receptor (AdR) inhibition, revealing a dual pro-angiogenic and immunosuppressive HOXD13 axis with therapeutic relevance.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"3 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109896","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}
Pub Date : 2026-02-03DOI: 10.1158/2159-8290.cd-nw2026-0010
Morning administration of checkpoint inhibitors significantly extended survival in patients with advanced non–small cell lung cancer, in the first randomized trial of immunotherapy timing. The results provide prospective support for aligning treatment with circadian biology as a simple way to improve cancer outcomes.
{"title":"Randomized Trial Links Time of Day to Immunotherapy Success","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0010","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0010","url":null,"abstract":"Morning administration of checkpoint inhibitors significantly extended survival in patients with advanced non–small cell lung cancer, in the first randomized trial of immunotherapy timing. The results provide prospective support for aligning treatment with circadian biology as a simple way to improve cancer outcomes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"19 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109894","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}
Pub Date : 2026-02-03DOI: 10.1158/2159-8290.cd-nw2026-0009
Five-year data from the phase IIb KEYNOTE-942 study show that the mRNA-based neoantigen vaccine intismeran autogene continues to reduce the risk of melanoma recurrence or death by roughly 49% when combined with pembrolizumab. This durability strengthens confidence in the personalized vaccine strategy, but a larger phase III trial will provide the decisive findings.
{"title":"Personalized Cancer Vaccine Shows Durable Benefit at 5 Years","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0009","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0009","url":null,"abstract":"Five-year data from the phase IIb KEYNOTE-942 study show that the mRNA-based neoantigen vaccine intismeran autogene continues to reduce the risk of melanoma recurrence or death by roughly 49% when combined with pembrolizumab. This durability strengthens confidence in the personalized vaccine strategy, but a larger phase III trial will provide the decisive findings.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109895","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}
Pub Date : 2026-02-02DOI: 10.1158/2159-8290.CD-RW2026-017
{"title":"Synthetic Storage of Transcripts Captures Hidden States Driving Drug Resistance.","authors":"","doi":"10.1158/2159-8290.CD-RW2026-017","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-RW2026-017","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"OF1"},"PeriodicalIF":33.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112467","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}
Pub Date : 2026-01-30DOI: 10.1158/2159-8290.cd-25-0859
Tomohiro Aoki,Gerben Duns,Shinya Rai,Aixiang Jiang,Andrew Lytle,Yifan Yin,Makoto Kishida,Michael Yu Li,Cecilia Lee,Denise Smorra,Laura K Hilton,Shannon Healy,Stefan K Alig,Mohammad Shahrokh Esfahani,Clementine Sarkozy,Stacy S Hung,Katy Milne,Adele Telenius,Luke O Brien,Jasper Ch Wong,Claudia Cassidy,Manabu Fujisawa,Celia Strong,Talia Goodyear,Chantal Di Vito,Cassandra Luksik,Glenn Edin,Laura Gonzalez,Juan Rangel Patiño,Michael Hong,Shaocheng Wu,Eric Lee,Ali Sakhdari,Katsuyoshi Takata,Tomoko Miyata-Takata,Merrill Boyle,Susana Ben-Neriah,Andrew P Weng,Alexander Xu,Akil Merchant,Andrew Roth,Michael Crump,John Kuruvilla,Anca Prica,Robert Kridel,David G Huntsman,Brad H Nelson,Pedro Farinha,Ryan D Morin,Ash A Alizadeh,Kerry J Savage,David W Scott,Christian Steidl
The tissue architecture of classic Hodgkin Lymphoma (CHL) is unique among cancers and characterized by rare malignant Hodgkin and Reed-Sternberg cells that co-evolve with a complex ecosystem of immune cells in the tumor microenvironment (TME). The lack of a comprehensive systems-level interrogation has hindered the description of disease heterogeneity and clinically relevant molecular subtypes. Here, we employed an integrative, multimodal approach to characterize CHL tumors using malignant cell sequencing, spatial transcriptomics and imaging mass cytometry. We identified four molecular subtypes (CST, CN913, STB, and CN2P), each characterized by distinct clinical features, mutational patterns, malignant cell gene expression profiles, and spatial architecture involving immune cell populations. Functional modeling of CSF2RB mutations, a characteristic feature of the CST subtype, revealed dysregulated oncogenic signaling and unique TME crosstalk. These findings highlight the significance of multi-dimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities.
{"title":"Multidimensional Characterization of Tumor-Immune Architecture Reveals Clinically Relevant Classic Hodgkin Lymphoma Subtypes.","authors":"Tomohiro Aoki,Gerben Duns,Shinya Rai,Aixiang Jiang,Andrew Lytle,Yifan Yin,Makoto Kishida,Michael Yu Li,Cecilia Lee,Denise Smorra,Laura K Hilton,Shannon Healy,Stefan K Alig,Mohammad Shahrokh Esfahani,Clementine Sarkozy,Stacy S Hung,Katy Milne,Adele Telenius,Luke O Brien,Jasper Ch Wong,Claudia Cassidy,Manabu Fujisawa,Celia Strong,Talia Goodyear,Chantal Di Vito,Cassandra Luksik,Glenn Edin,Laura Gonzalez,Juan Rangel Patiño,Michael Hong,Shaocheng Wu,Eric Lee,Ali Sakhdari,Katsuyoshi Takata,Tomoko Miyata-Takata,Merrill Boyle,Susana Ben-Neriah,Andrew P Weng,Alexander Xu,Akil Merchant,Andrew Roth,Michael Crump,John Kuruvilla,Anca Prica,Robert Kridel,David G Huntsman,Brad H Nelson,Pedro Farinha,Ryan D Morin,Ash A Alizadeh,Kerry J Savage,David W Scott,Christian Steidl","doi":"10.1158/2159-8290.cd-25-0859","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0859","url":null,"abstract":"The tissue architecture of classic Hodgkin Lymphoma (CHL) is unique among cancers and characterized by rare malignant Hodgkin and Reed-Sternberg cells that co-evolve with a complex ecosystem of immune cells in the tumor microenvironment (TME). The lack of a comprehensive systems-level interrogation has hindered the description of disease heterogeneity and clinically relevant molecular subtypes. Here, we employed an integrative, multimodal approach to characterize CHL tumors using malignant cell sequencing, spatial transcriptomics and imaging mass cytometry. We identified four molecular subtypes (CST, CN913, STB, and CN2P), each characterized by distinct clinical features, mutational patterns, malignant cell gene expression profiles, and spatial architecture involving immune cell populations. Functional modeling of CSF2RB mutations, a characteristic feature of the CST subtype, revealed dysregulated oncogenic signaling and unique TME crosstalk. These findings highlight the significance of multi-dimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"164 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089062","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}
Pub Date : 2026-01-29DOI: 10.1158/2159-8290.cd-rw2026-015
{"title":"Dual Targeting of TGFβ1 and PD-1 Is Safe and Tolerable in Solid Tumors.","authors":"","doi":"10.1158/2159-8290.cd-rw2026-015","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-rw2026-015","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"2 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089063","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}
Pub Date : 2026-01-28DOI: 10.1158/2159-8290.cd-rw2026-014
{"title":"vCATCH Maps Cellular Targets of Cancer Drugs throughout the Entire Body.","authors":"","doi":"10.1158/2159-8290.cd-rw2026-014","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-rw2026-014","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"82 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089064","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}
Pub Date : 2026-01-27DOI: 10.1158/2159-8290.cd-nw2026-0008
An AI system powered by structured oncology data matched oncologists' treatment choices in more than 90% of real clinical queries, besting a standard large language model. By focusing on a narrowly defined task-genomics-guided therapy selection-the platform demonstrates a practical pathway for deploying reliable AI tools in precision oncology.
{"title":"AI Matches Treatment Choices in Precision Oncology Tests.","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0008","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0008","url":null,"abstract":"An AI system powered by structured oncology data matched oncologists' treatment choices in more than 90% of real clinical queries, besting a standard large language model. By focusing on a narrowly defined task-genomics-guided therapy selection-the platform demonstrates a practical pathway for deploying reliable AI tools in precision oncology.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"293 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056821","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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