Nature cancer最新文献

{"title":"Targeting BRCA1-deficient PARP inhibitor-resistant cells with nickases reveals nick resection as a cancer vulnerability.","authors":"Jenna M Whalen, Jillian Earley, Christi Wisniewski, Arthur M Mercurio, Sharon B Cantor","doi":"10.1038/s43018-024-00902-1","DOIUrl":"10.1038/s43018-024-00902-1","url":null,"abstract":"<p><p>Tumors lacking the BRCA1 and BRCA2 (BRCA) hereditary breast cancer genes display heightened sensitivity to anti-cancer treatments, such as inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). However, when resistance develops, treatments are lacking. Using CRISPR technology, we discovered that enhancing homologous recombination through increased DNA end resection in BRCA1-deficient cells by loss of the 53BP1-Shieldin complex-which is associated with resistance to PARP inhibitors-also heightens sensitivity to DNA nicks. The sensitivity is caused by hyper-resection of nicks into extensive single-stranded regions that trigger cell death. Based on these findings and that nicks limit tumor formation in mice, we propose nickases as a tool for personalized medicine. Moreover, our findings indicate that restricting nick expansion is a critical function of the 53BP1-Shieldin complex.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008607","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}

{"title":"Refining biomarker design in light of cancer evolution","authors":"","doi":"10.1038/s43018-024-00884-0","DOIUrl":"10.1038/s43018-024-00884-0","url":null,"abstract":"Insights from the TRACERx cohort suggest that the ORACLE biomarker might help to improve molecular prognostication in patients with lung tumors by accounting for spatiogenomic intratumor heterogeneity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"20-21"},"PeriodicalIF":23.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008605","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}

{"title":"Publisher Correction: TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation.","authors":"Katherine Nutsch, Karl L Banta, Thomas D Wu, Charles W Tran, Stephanie Mittman, Ellen Duong, Barzin Y Nabet, Yan Qu, Katherine Williams, Sören Müller, Namrata S Patil, Eugene Y Chiang, Ira Mellman","doi":"10.1038/s43018-025-00908-3","DOIUrl":"https://doi.org/10.1038/s43018-025-00908-3","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008602","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}

{"title":"Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.","authors":"Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver","doi":"10.1038/s43018-024-00895-x","DOIUrl":"https://doi.org/10.1038/s43018-024-00895-x","url":null,"abstract":"<p><p>Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008606","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}

{"title":"Fine-tuning tumor immunogenicity with mitochondrial complex I.","authors":"Désirée Schatton, Christian Frezza","doi":"10.1038/s43018-024-00874-2","DOIUrl":"https://doi.org/10.1038/s43018-024-00874-2","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008599","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}

{"title":"First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer.","authors":"Ramona Rudalska, Jule Harbig, Michael Forster, Pascal Woelffing, Aylin Esposito, Mark Kudolo, Adelina Botezatu, Vanessa Haller, Nicole Janssen, Samuel Holzmayer, Philipp Nahidino, Omelyan Trompak, Tatu Pantsar, Thales Kronenberger, Can Yurttas, Elke Rist, Alexander N R Weber, Marc H Dahlke, German Ott, Alfred Koenigsrainer, Ulrich Rothbauer, Melanie Maerklin, Thomas Muerdter, Matthias Schwab, Stephan Singer, Lars Zender, Stefan Laufer, Daniel Dauch","doi":"10.1038/s43018-024-00899-7","DOIUrl":"https://doi.org/10.1038/s43018-024-00899-7","url":null,"abstract":"<p><p>Colorectal cancer (CRC) constitutes the second leading cause of cancer-related death worldwide and advanced CRCs are resistant to targeted therapies, chemotherapies and immunotherapies. p38α (Mapk14) has been suggested as a therapeutic target in CRC; however, available p38α inhibitors only allow for insufficient target inhibition. Here we describe a unique class of p38α inhibitors with ultralong target residence times (designated ULTR-p38i) that robustly inhibit p38α downstream signaling and induce distinct biological phenotypes. ULTR-p38i monotherapy triggers an uncontrolled mitotic entry by activating Cdc25 and simultaneously blocking Wee1. Consequently, CRC cells undergo mitotic catastrophe, resulting in apoptosis or senescence. ULTR-p38i exhibit high selectivity, good pharmaco-kinetic properties and no measurable toxicity with strong therapeutic effects in patient-derived CRC organoids and syngeneic CRC mouse models. Conceptually, our study suggests ultralong-target-residence-time kinase inhibitors as an alternative to covalent inhibitors, which, because of the lack of cysteine residues, cannot be generated for many kinase cancer targets.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008600","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}

{"title":"Efficacy and tolerability of neoadjuvant therapy with Talimogene laherparepvec in cutaneous basal cell carcinoma: a phase II trial (NeoBCC trial)","authors":"Julia Maria Ressler,&nbsp;Maud Plaschka,&nbsp;Rita Silmbrod,&nbsp;Victoria Bachmayr,&nbsp;Lisa Ellen Shaw,&nbsp;Thomas Silly,&nbsp;Nina Zila,&nbsp;Andreas Stepan,&nbsp;Anna Kusienicka,&nbsp;Philipp Tschandl,&nbsp;Julia Tittes,&nbsp;Florian Roka,&nbsp;Werner Haslik,&nbsp;Peter Petzelbauer,&nbsp;Franz Koenig,&nbsp;Rainer Kunstfeld,&nbsp;Matthias Farlik,&nbsp;Florian Halbritter,&nbsp;Wolfgang Weninger,&nbsp;Christoph Hoeller","doi":"10.1038/s43018-024-00879-x","DOIUrl":"10.1038/s43018-024-00879-x","url":null,"abstract":"We present a single-arm, phase II, neoadjuvant trial with the oncolytic virus talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect cutaneous basal cell carcinomas. The primary end point, defined as the proportion of patients, who after six cycles of T-VEC (13 weeks), become resectable without the need for plastic reconstructive surgery, was already achieved after stage I (9 of 18 patients; 50.0%); thus the study was discontinued for early success. The objective response rate was 55.6% and the complete pathological response rate was 33.3%. Secondary end points included safety, relapse-free survival and overall survival, time to occurrence of new basal cell carcinomas and biological read outs. Only mild adverse events occurred. The 6-month relapse-free survival and overall survival rates were 100%. In two patients a new basal cell carcinoma was diagnosed. T-VEC led to a significant increase in cytotoxic T cells (P = 0.0092), B cells (P = 0.0004) and myeloid cells (P = 0.0042) and a decrease in regulatory T cells (P = 0.0290) within the tumor microenvironment. Together, neoadjuvant T-VEC represents a viable treatment option for patients with difficult-to-resect basal cell carcinomas (EudraCT no. 2018-002165-19). Ressler et al. perform a phase II clinical trial of neoadjuvant talimogene laherparepvec in cutaneous basal cell carcinoma and report on treatment safety, efficacy and on treatment-induced immune tumor microenvironment changes.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"51-66"},"PeriodicalIF":23.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008598","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}

{"title":"Neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in women with early HER2-positive breast cancer: the randomized phase 2 ABCSG-52/ATHENE trial","authors":"Gabriel Rinnerthaler,&nbsp;Daniel Egle,&nbsp;Rupert Bartsch,&nbsp;Clemens A. Schmitt,&nbsp;Andreas Petzer,&nbsp;Marija Balic,&nbsp;Edgar Petru,&nbsp;Ursula Denison,&nbsp;Christian F. Singer,&nbsp;Vesna Bjelic-Radisic,&nbsp;Simon Peter Gampenrieder,&nbsp;Michael Knauer,&nbsp;Karl Sotlar,&nbsp;Christine Brunner,&nbsp;Florian Posch,&nbsp;Dominik Hlauschek,&nbsp;Lidija Sölkner,&nbsp;Zsuzsanna Bago-Horvath,&nbsp;Martin Filipits,&nbsp;Manuela Gili,&nbsp;Magdalena Ritter,&nbsp;Verena Wieser,&nbsp;Carmen Albertini,&nbsp;Nadja Zaborsky,&nbsp;Lukas Weiss,&nbsp;Maximilian Marhold,&nbsp;Bruno Schneeweiss,&nbsp;Renate Pusch,&nbsp;Michael Gnant,&nbsp;Richard Greil","doi":"10.1038/s43018-024-00890-2","DOIUrl":"10.1038/s43018-024-00890-2","url":null,"abstract":"The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no. 2019-002364-27), we investigated epirubicin plus immunotherapy in women with human epidermal growth factor receptor 2 (HER2)-positive EBC. A total of 58 patients were randomized 1:1 to two cycles of a chemotherapy-free induction phase (part 1) of dual HER2 blockade with trastuzumab and pertuzumab (TP) plus the anti-programmed death ligand 1 antibody atezolizumab (TP-A) or TP alone. Thereafter, all patients received four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint, pathological complete response (pCR), was met in 35 patients (60.3%; 95% confidence interval (CI) 47.5% to 71.9%), 19 patients (65.5%) in the TP-A group and 16 patients (55.2%) in the TP group. The residual cancer burden 0/I rate and objective response rate (secondary endpoints) in all patients with evaluable data were 80.0% (n = 44/55; 95% CI 67.6% to 88.4%) and 89.3% (n = 50/56; 95% CI 78.5% to 95.0%), respectively. Grade ≥3 adverse events were reported in 17 patients (29.3%). Based on our findings, we conclude that a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is effective and safe in patients with HER2-positive EBC. Rinnerthaler et al. perform a randomized phase 2 trial of neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in patients with early HER2-positive breast cancer and report positively on efficacy and safety.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 1","pages":"41-50"},"PeriodicalIF":23.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008601","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}

{"title":"ETV7 limits the antiviral and antitumor efficacy of CD8⁺ T cells by diverting their fate toward exhaustion.","authors":"Jie Cheng, Yifeng Xiao, Ting Peng, Zijian Zhang, You Qin, Yuqian Wang, Jiangzhou Shi, Jinxin Yan, Zihao Zhao, Liangtao Zheng, Zhijun He, Jianwei Wang, Zemin Zhang, Cheng Li, Haichuan Zhu, Peng Jiang","doi":"10.1038/s43018-024-00892-0","DOIUrl":"https://doi.org/10.1038/s43018-024-00892-0","url":null,"abstract":"<p><p>Terminal exhaustion is a critical barrier to antitumor immunity. By integrating and analyzing single-cell RNA-sequencing and single-cell assay for transposase-accessible chromatin with sequencing data, we found that ETS variant 7 (ETV7) is indispensable for determining CD8⁺ T cell fate in tumors. ETV7 introduction drives T cell differentiation from memory to terminal exhaustion, limiting antiviral and antitumor efficacy in male mice. Mechanistically, ETV7 acts as a central transcriptional node by binding to specific memory genes and exhaustion genes and functionally skewing these transcriptional programs toward exhaustion. Clinically, ETV7 expression is negatively correlated with progression and responsiveness to immune checkpoint blockade in various human cancers. ETV7 depletion strongly enhances the antitumor efficacy of CD8⁺ T cells and engineered chimeric antigen receptor T cells in solid tumors. Thus, these findings demonstrate a decisive role for ETV7 in driving CD8⁺ T cell terminal exhaustion and reveal that ETV7 may be a promising target and biomarker for improving the efficacy of cancer immunotherapy.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979203","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}

{"title":"ERα dysfunction caused by ESR1 mutations and therapeutic pressure promotes lineage plasticity in ER⁺ breast cancer.","authors":"Jackson Liang, Xiaosai Yao, Patrick Aouad, Bu-Er Wang, Lisa Crocker, Subhra Chaudhuri, Yuxin Liang, Spyros Darmanis, Jennifer Giltnane, Heather M Moore, Junko Aimi, Ching-Wei Chang, Mary R Gates, Jennifer Eng-Wong, Marc Hafner, Ciara Metcalfe","doi":"10.1038/s43018-024-00898-8","DOIUrl":"10.1038/s43018-024-00898-8","url":null,"abstract":"<p><p>Multiple next-generation molecules targeting estrogen receptor α (ERα) are being investigated in breast cancer clinical trials, encompassing thousands of women globally. Development of these molecules was partly motivated by the discovery of resistance-associated mutations in ESR1 (encodes ERα). Here, we studied the impact of ERα antagonist/degraders against Esr1 mutations expressed in mouse mammary glands. Inhibition of mutant ERα induced mixed-lineage cells, characterized by aberrant co-engagement of normally disparate master transcription factors. Lineage infidelity was also observed in Esr1-wild-type mice upon long-term estrogen deprivation. In ER⁺ breast cancer biopsy specimens, heavily pretreated tumors with no ESR1 mutation detected (NMD) frequently exhibited mixed-lineage features. ESR1-mutant tumors generally retained luminal features and higher ERα activity and exhibited an anti-proliferative response to the ERα antagonist giredestrant. ESR1-mutant tumors acquired mixed-lineage features following treatment. Lineage heterogeneity in advanced ER⁺ breast cancer may underpin the differential benefit of investigational ERα therapeutics observed in ESR1-mutant versus NMD contexts.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979201","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}