Although immune checkpoint inhibitors (ICIs) show durable responses in various cancers, relapse remains common. The efficacy of retreatment with ICIs is controversial. We conducted a multicenter, single-arm, phase 2 trial (NCT05824468) including 30 advanced cervical cancer patients that progressed on or after prior ICI therapy. Participants received a combined regimen of zimberelimab and lenvatinib (immune rechallenge). Single-cell multi-omics analysis of sequential biopsies of relapsed tumors and blood samples showed immune rechallenge induced a more cytotoxic phenotype in CD8+T cells in responders, while an NK-like CD8+T and progenitor-exhausted CD8+T phenotype in the blood of non-responders. In tumor, responders showed more effector memory CD8+T cells and reduced exhausted CD8+T cell post-treatment. A population of CD45+CD3+Lyz+dyad cells, composed of T cells and myeloid cells, was correlated with clinical benefit. Our findings proved immune rechallenge could be an effective treatment for patients with advanced cervical cancer who progressed on or after prior ICIs therapy.
{"title":"Spatiotemporal Immune Determinants of Response to Immune Rechallenge in Advanced Cervical Cancer.","authors":"Chunyan Lan,Peidong Zhang,Jing Zhao,Qiaqia Li,Peiwei Li,Jundong Li,Min Zheng,Yin Wang,Ruiming Tang,Huazhen Wu,Haixi Liang,Lin Zhou,Zhiwen Xie,Xiaoli Feng,Huisi Qiu,Linjie Zhao,Xin Huang,Shengtao Zhou","doi":"10.1158/2159-8290.cd-25-0467","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0467","url":null,"abstract":"Although immune checkpoint inhibitors (ICIs) show durable responses in various cancers, relapse remains common. The efficacy of retreatment with ICIs is controversial. We conducted a multicenter, single-arm, phase 2 trial (NCT05824468) including 30 advanced cervical cancer patients that progressed on or after prior ICI therapy. Participants received a combined regimen of zimberelimab and lenvatinib (immune rechallenge). Single-cell multi-omics analysis of sequential biopsies of relapsed tumors and blood samples showed immune rechallenge induced a more cytotoxic phenotype in CD8+T cells in responders, while an NK-like CD8+T and progenitor-exhausted CD8+T phenotype in the blood of non-responders. In tumor, responders showed more effector memory CD8+T cells and reduced exhausted CD8+T cell post-treatment. A population of CD45+CD3+Lyz+dyad cells, composed of T cells and myeloid cells, was correlated with clinical benefit. Our findings proved immune rechallenge could be an effective treatment for patients with advanced cervical cancer who progressed on or after prior ICIs therapy.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"29 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937772","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 : 2026-01-09DOI: 10.1158/2159-8290.cd-rw2026-002
{"title":"pTɑ Enhances CAR T-cell Function to Eradicate Liquid and Solid Tumors.","authors":"","doi":"10.1158/2159-8290.cd-rw2026-002","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-rw2026-002","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"82 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949631","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 : 2026-01-09DOI: 10.1158/2159-8290.cd-rw2026-003
{"title":"Genetic Context Shapes Selection or Decay of Driver Mutations in Colon Cancer.","authors":"","doi":"10.1158/2159-8290.cd-rw2026-003","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-rw2026-003","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"255 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949630","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 : 2026-01-08DOI: 10.1158/2159-8290.cd-25-1761
Ferran Fece de la Cruz, Andreas Varkaris, Parasvi S. Patel, Elijah W. Kushner, Alvin A. Morales-Giron, Sangmi Sandra. Lee, Ankit Singh, Clara T. Kim, Bryanna L. Norden, Sara Ehnstrom, Jakob M. Riedl, Jacquelyn M. Curtis, Haley Barnes, Allison M. Kehlmann, Nicholas J. Chevalier, Hitomi S. Okuma, Manisha Patel, Lori J. Wirth, Brendan Connell, Francis Nugent, Leontios Pappas, Kayao Lau, Dejan Juric, Jessica L. Hopkins, Keelan Z. Guiley, Kevan M. Shokat, Doga C. Gulhan, Aparna R. Parikh, Ryan B. Corcoran
The tumor suppressor TP53 is the most frequently altered gene in cancer, and the Y220C hotspot, found in 1.8% of TP53-mutant tumors, creates a druggable cavity that destabilizes p53. Rezatapopt, a first-in-class, orally bioavailable reactivator of Y220C-mutant p53, has demonstrated promising initial efficacy in the phase 1/2 PYNNACLE trial. We report the first clinical mechanisms of resistance to this therapeutic class. Profiling of circulating tumor DNA, tumor biopsies, and rapid autopsy specimens upon rezatapopt progression revealed multiple heterogenous secondary TP53 alterations in cis with Y220C, including: (1) DNA-binding domain mutations or frameshift/nonsense mutations that abolish transcriptional activity, and (2) mutations within the Y220C binding surface predicted to hinder drug binding. Functional modeling confirmed these double mutants eliminate p53 reactivation and target gene induction by rezatapopt. These findings establish a molecular framework for resistance to p53 Y220C reactivators and inform strategies to overcome resistance with next-generation agents.
{"title":"Acquired on-target alterations drive clinical resistance to p53-Y220C reactivators","authors":"Ferran Fece de la Cruz, Andreas Varkaris, Parasvi S. Patel, Elijah W. Kushner, Alvin A. Morales-Giron, Sangmi Sandra. Lee, Ankit Singh, Clara T. Kim, Bryanna L. Norden, Sara Ehnstrom, Jakob M. Riedl, Jacquelyn M. Curtis, Haley Barnes, Allison M. Kehlmann, Nicholas J. Chevalier, Hitomi S. Okuma, Manisha Patel, Lori J. Wirth, Brendan Connell, Francis Nugent, Leontios Pappas, Kayao Lau, Dejan Juric, Jessica L. Hopkins, Keelan Z. Guiley, Kevan M. Shokat, Doga C. Gulhan, Aparna R. Parikh, Ryan B. Corcoran","doi":"10.1158/2159-8290.cd-25-1761","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1761","url":null,"abstract":"The tumor suppressor TP53 is the most frequently altered gene in cancer, and the Y220C hotspot, found in 1.8% of TP53-mutant tumors, creates a druggable cavity that destabilizes p53. Rezatapopt, a first-in-class, orally bioavailable reactivator of Y220C-mutant p53, has demonstrated promising initial efficacy in the phase 1/2 PYNNACLE trial. We report the first clinical mechanisms of resistance to this therapeutic class. Profiling of circulating tumor DNA, tumor biopsies, and rapid autopsy specimens upon rezatapopt progression revealed multiple heterogenous secondary TP53 alterations in cis with Y220C, including: (1) DNA-binding domain mutations or frameshift/nonsense mutations that abolish transcriptional activity, and (2) mutations within the Y220C binding surface predicted to hinder drug binding. Functional modeling confirmed these double mutants eliminate p53 reactivation and target gene induction by rezatapopt. These findings establish a molecular framework for resistance to p53 Y220C reactivators and inform strategies to overcome resistance with next-generation agents.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"392 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920234","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 : 2026-01-07DOI: 10.1158/2159-8290.cd-rw2026-001
{"title":"Bacterial Elements Detected in Brain Tumors May Shape Tumor Microenvironment.","authors":"","doi":"10.1158/2159-8290.cd-rw2026-001","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-rw2026-001","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"265 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949632","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 : 2026-01-05DOI: 10.1158/2159-8290.cd-25-1085
Michael Lee,Yuannyu Zhang,Jun Yi Stanley Lim,Tao Dai,James Ye,Margaret B Cervantes,Varun Sondhi,Sisi Zheng,Yoon Jung Kim,Brandon Chen,Ralph J DeBerardinis,Jian Xu
Retrotransposons are genomic parasites frequently reactivated in cancers, where their mobility can cause genetic alterations. However, it remains unclear whether their gene products contribute to cancer beyond mutagenesis. Here, we uncover a chromatin-associated function of RNAs from Long Interspersed Element-1 (LINE-1), the only autonomous retrotransposon in the human genome. Subcellular-resolved transcriptomics revealed that LINE-1 RNAs are primarily nascent transcripts produced by full-length, cell-type-specific genomic copies of evolutionarily young subfamilies. Using a long-read chromosome conformation assay, we identified a class of highly interactive LINE-1 loci required for gene expression across cancer subtypes, revealing an unexpected regulatory role for LINE-1 locus transcription in oncogenic gene control. LINE-1 RNA depletion disrupted LINE-1-centric chromatin interactions and downregulated associated genes, whereas genomic insertion of an inducible LINE-1 generated de novo chromatin interactions in a transcription-dependent manner. Therefore, beyond their mutagenic potential, retrotransposons also regulate cancer gene expression by nucleating chromatin architecture through their transcriptional activity.
{"title":"LINE-1 Locus Transcription Nucleates Oncogenic Chromatin Architecture.","authors":"Michael Lee,Yuannyu Zhang,Jun Yi Stanley Lim,Tao Dai,James Ye,Margaret B Cervantes,Varun Sondhi,Sisi Zheng,Yoon Jung Kim,Brandon Chen,Ralph J DeBerardinis,Jian Xu","doi":"10.1158/2159-8290.cd-25-1085","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1085","url":null,"abstract":"Retrotransposons are genomic parasites frequently reactivated in cancers, where their mobility can cause genetic alterations. However, it remains unclear whether their gene products contribute to cancer beyond mutagenesis. Here, we uncover a chromatin-associated function of RNAs from Long Interspersed Element-1 (LINE-1), the only autonomous retrotransposon in the human genome. Subcellular-resolved transcriptomics revealed that LINE-1 RNAs are primarily nascent transcripts produced by full-length, cell-type-specific genomic copies of evolutionarily young subfamilies. Using a long-read chromosome conformation assay, we identified a class of highly interactive LINE-1 loci required for gene expression across cancer subtypes, revealing an unexpected regulatory role for LINE-1 locus transcription in oncogenic gene control. LINE-1 RNA depletion disrupted LINE-1-centric chromatin interactions and downregulated associated genes, whereas genomic insertion of an inducible LINE-1 generated de novo chromatin interactions in a transcription-dependent manner. Therefore, beyond their mutagenic potential, retrotransposons also regulate cancer gene expression by nucleating chromatin architecture through their transcriptional activity.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"4 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897445","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 : 2025-12-31DOI: 10.1158/2159-8290.cd-nw2025-0118
Patients with relapsed or refractory follicular lymphoma have few treatment options-with a rituximab-lenalidomide (R2) pairing considered the only alternative to immunochemotherapy. But data from the pivotal phase III EPCORE LF-1 trial show that a three-drug combination of epcoritimab plus R2 can reduce the risk of disease progression and death by 79% compared with R2 alone.
{"title":"Epcoritimab Combo Could Be New Standard for Some FLs.","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0118","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0118","url":null,"abstract":"Patients with relapsed or refractory follicular lymphoma have few treatment options-with a rituximab-lenalidomide (R2) pairing considered the only alternative to immunochemotherapy. But data from the pivotal phase III EPCORE LF-1 trial show that a three-drug combination of epcoritimab plus R2 can reduce the risk of disease progression and death by 79% compared with R2 alone.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"4 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897448","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 : 2025-12-31DOI: 10.1158/2159-8290.CD-24-0853
Dennis J Yuan, John Zinno, Theo Botella, Dalia Dhingra, Shu Wang, Allegra G Hawkins, Ariel Swett, Jesus Sotelo, Ramya Raviram, Clayton Hughes, Catherine Potenski, Katharine D Godfrey, Kara M Ainsworth, Shuzhen Xu, Jianwen Que, Julian A Abrams, Akira Yokoyama, Nobuyuki Kakiuchi, Seishi Ogawa, Dan A Landau
Somatic mosaicism is pervasively observed in human aging, with clonal expansions of cells harboring mutations in recurrently mutated driver genes. Bulk sequencing of tissues captures mutation frequencies, but cannot reconstruct clonal architectures nor delineate how driver mutations impact cellular phenotypes. We developed single-cell Genotype-to-Phenotype sequencing (scG2P) for high-throughput, highly-multiplexed, joint capture of genotyping of mutation hotspots and mRNA markers. We applied scG2P to aged esophagus samples from six individuals and observed large numbers of clones with a single driver event, accompanied by rare clones with two driver mutations. NOTCH1 mutants dominate the clonal landscape and are linked to stunted epithelial differentiation, while TP53 mutants promote clonal expansion through both differentiation biases and increased cell cycling. Thus, joint single-cell highly multiplexed capture of somatic mutations and mRNA transcripts enables high resolution reconstruction of clonal architecture and associated phenotypes in solid tissue somatic mosaicism.
{"title":"Genotype-to-phenotype mapping of somatic clonal mosaicism via single-cell co-capture of DNA mutations and mRNA transcripts.","authors":"Dennis J Yuan, John Zinno, Theo Botella, Dalia Dhingra, Shu Wang, Allegra G Hawkins, Ariel Swett, Jesus Sotelo, Ramya Raviram, Clayton Hughes, Catherine Potenski, Katharine D Godfrey, Kara M Ainsworth, Shuzhen Xu, Jianwen Que, Julian A Abrams, Akira Yokoyama, Nobuyuki Kakiuchi, Seishi Ogawa, Dan A Landau","doi":"10.1158/2159-8290.CD-24-0853","DOIUrl":"10.1158/2159-8290.CD-24-0853","url":null,"abstract":"<p><p>Somatic mosaicism is pervasively observed in human aging, with clonal expansions of cells harboring mutations in recurrently mutated driver genes. Bulk sequencing of tissues captures mutation frequencies, but cannot reconstruct clonal architectures nor delineate how driver mutations impact cellular phenotypes. We developed single-cell Genotype-to-Phenotype sequencing (scG2P) for high-throughput, highly-multiplexed, joint capture of genotyping of mutation hotspots and mRNA markers. We applied scG2P to aged esophagus samples from six individuals and observed large numbers of clones with a single driver event, accompanied by rare clones with two driver mutations. NOTCH1 mutants dominate the clonal landscape and are linked to stunted epithelial differentiation, while TP53 mutants promote clonal expansion through both differentiation biases and increased cell cycling. Thus, joint single-cell highly multiplexed capture of somatic mutations and mRNA transcripts enables high resolution reconstruction of clonal architecture and associated phenotypes in solid tissue somatic mosaicism.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":33.3,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892093","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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