Cancer discoveryPub Date : 2025-07-03DOI: 10.1158/2159-8290.cd-25-0666
Isabella Del Priore, Alex Toker
{"title":"Lessons from the Oncology Clinic: Repurposing PI3K Pathway Inhibitors for the Treatment of PTEN Hamartoma Tumor Syndrome","authors":"Isabella Del Priore, Alex Toker","doi":"10.1158/2159-8290.cd-25-0666","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0666","url":null,"abstract":"Summary: The underlying genetic abnormalities that cause the phenotypic variation seen in patients with PTEN hamartoma tumor syndrome (PHTS) are poorly understood. In this issue, Castillo and colleagues report that the somatic loss of PTEN through copy-neutral loss of heterozygosity and the resulting uniparental disomy in endothelial cells lead to vascular malformations in PHTS, which respond to PI3K/AKT/mTOR pathway inhibitors. See related article by Castillo et al., p. 1350 .","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"7 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547489","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}
Cancer discoveryPub Date : 2025-07-03DOI: 10.1158/2159-8290.CD-24-0807
Sandra D Castillo, Xabier Perosanz, Andrew K Ressler, Marta Ivars, Jairo Rodríguez, Carlota Rovira, Emanuele M Nola, Judith Llena, Joaquim Grego-Bessa, Mónica Roldán, Raquel Arnau, Anabel Martínez-Romero, Ignasi Barber, Miguel Bejarano, Asunción Vicente, Verónica Celis, Héctor Salvador, Jaume Mora, Douglas A Marchuk, Eulalia Baselga, Mariona Graupera
{"title":"Somatic Uniparental Disomy of PTEN in Endothelial Cells Causes Vascular Malformations in Patients with PTEN Hamartoma Tumor Syndrome.","authors":"Sandra D Castillo, Xabier Perosanz, Andrew K Ressler, Marta Ivars, Jairo Rodríguez, Carlota Rovira, Emanuele M Nola, Judith Llena, Joaquim Grego-Bessa, Mónica Roldán, Raquel Arnau, Anabel Martínez-Romero, Ignasi Barber, Miguel Bejarano, Asunción Vicente, Verónica Celis, Héctor Salvador, Jaume Mora, Douglas A Marchuk, Eulalia Baselga, Mariona Graupera","doi":"10.1158/2159-8290.CD-24-0807","DOIUrl":"10.1158/2159-8290.CD-24-0807","url":null,"abstract":"<p><p>PTEN hamartoma tumor syndrome (PHTS) is a rare tumor risk disorder caused by germline loss-of-function mutations in PTEN. Half of these patients develop vascular malformations, a hamartoma characterized by overgrowth of vessels. In this study, we harness biopsies and patient-derived endothelial cells (EC) to study the genetic etiology of PHTS-related vascular malformations. We discover that these lesions are generated by somatic loss of the PTEN wild-type allele through copy-neutral loss of heterozygosity, leading to somatic uniparental disomy of the PTEN-mutated allele in ECs. We established a mouse model of PHTS-related vascular malformations and identified that the mTOR inhibitor rapamycin and AKT inhibitor capivasertib block vascular lesion growth. As proof-of-concept for clinical activity, off-label treatment with rapamycin of two patients with PHTS reduced vascular overgrowth and abrogated lesion-associated pain. Overall, our results uncover the genetic cause of vascular malformations in patients with PHTS and open new avenues for therapeutic intervention.</p><p><strong>Significance: </strong>Somatic loss of PTEN in ECs causes vascular malformations in patients with the tumor risk syndrome PHTS. These lesions respond to PI3K signaling inhibition. See related commentary by Del Prior and Toker, p. 1306.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1350-1362"},"PeriodicalIF":29.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728708","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}
Cancer discoveryPub Date : 2025-07-03DOI: 10.1158/2159-8290.cd-25-0680
Christopher G. Cann, Cathy Eng
{"title":"Cancer in the Prime of Life: Etiologic Insights and Supportive Oncologic Interventions for the Rising Burden of Young Adult Cancer","authors":"Christopher G. Cann, Cathy Eng","doi":"10.1158/2159-8290.cd-25-0680","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0680","url":null,"abstract":"Summary: Shiels and colleagues analyzed the incidence data from the US Cancer Statistics Database and death certificate data from the National Center for Health Statistics to depict the incidence and mortality trends across both early-onset and average age–onset patients diagnosed with cancer over the past decade, with the objective to refine the understanding of etiologic factors and exposures that may be driving the observed increase in early-onset cancer. Their approach revealed that the majority of early-onset cancer diagnoses occurred in females; there was a significant increase in multiple cancers, most significantly in breast cancer and colon cancer; and although mortality did not increase across the entire early-onset population, mortality rates increased within colorectal, uterine, and testicular cancers. See related article by Shiels et al., p. 1363 .","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"27 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547484","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}
Cancer discoveryPub Date : 2025-07-03DOI: 10.1158/2159-8290.CD-24-1378
Nitin H Shirole, Devishi Kesar, Yenarae Lee, Amy Goodale, Sudeepa Syamala, Shweta Kukreja, Rong Li, Xintao Qiu, Wenyu Yu, Seth Goldman, Paloma Cejas, Henry W Long, Karen Adelman, John G Doench, William R Sellers, William G Kaelin
{"title":"Requirement for Cyclin D1 Underlies Cell-Autonomous HIF2 Dependence in Kidney Cancer.","authors":"Nitin H Shirole, Devishi Kesar, Yenarae Lee, Amy Goodale, Sudeepa Syamala, Shweta Kukreja, Rong Li, Xintao Qiu, Wenyu Yu, Seth Goldman, Paloma Cejas, Henry W Long, Karen Adelman, John G Doench, William R Sellers, William G Kaelin","doi":"10.1158/2159-8290.CD-24-1378","DOIUrl":"10.1158/2159-8290.CD-24-1378","url":null,"abstract":"<p><p>Inactivation of the VHL gene stabilizes HIF2α, which drives clear-cell renal cell carcinoma (ccRCC). The HIF2α inhibitor belzutifan is approved for ccRCC treatment, but de novo and acquired resistance are common. HIF2α, bound to ARNT, transcriptionally activates many genes. We performed CRISPR-mediated gene activation screens in HIF2α-dependent ccRCC lines treated with a belzutifan analog to identify HIF2α-responsive genes that confer cell-autonomous belzutifan resistance when not downregulated. Sustaining the expression of the HIF2α target gene CCND1, encoding cyclin D1, promoted HIF2α independence/belzutifan resistance. This activity requires CDK4/6 activation by cyclin D1 but is not solely due to phosphorylation of the canonical cyclin D1 target, pRB. Indeed, ccRCC lines lacking all three pRB family members remained at least partially HIF2α-dependent. In this context, however, a kinase-defective cyclin D1 variant partially overrode belzutifan's antiproliferative effects, suggesting that ccRCC promotion by cyclin D1 requires the phosphorylation of pRB paralogs and one or more kinase-independent cyclin D1 activities.</p><p><strong>Significance: </strong>We discovered that cyclin D1 is the key target of HIF2 driving the cell-autonomous proliferation of VHL-mutant kidney cancers and that cyclin D1 has targets beyond pRB in this setting. These findings have implications for treating kidney cancer with HIF2 inhibitors, alone or in combination with CDK4/6 inhibitors.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1484-1504"},"PeriodicalIF":29.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771172","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}
Cancer discoveryPub Date : 2025-07-03DOI: 10.1158/2159-8290.cd-25-0698
John J.Y. Lee, Mario L. Suvà
{"title":"Malignant Transformation of Glioblastoma: One Step at a Time","authors":"John J.Y. Lee, Mario L. Suvà","doi":"10.1158/2159-8290.cd-25-0698","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0698","url":null,"abstract":"Summary: In this issue of Cancer Discovery, Kim and colleagues characterize the transcriptional and epigenomic changes associated with gradual transformation of murine subventricular zone neural stem cells into glioblastoma, identifying an intermediary precancerous stage. Analysis of human glioblastoma and tumor-free subventricular zone tissues hints at the presence of precancerous cells with transcriptional similarity to murine precancerous cells and distinct aneuploidy from the bulk tumor. See related article by Kim et al., p. 1377","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"35 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546971","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}
Cancer discoveryPub Date : 2025-06-24DOI: 10.1158/2159-8290.cd-24-0684
Aarthi Venkat,Scott E Youlten,Beatriz P San Juan,Carley A Purcell,Shabarni Gupta,Matthew Amodio,Daniel P Neumann,John G Lock,Anton E Westacott,Cerys S McCool,Daniel B Burkhardt,Andrew Benz,Annelie Mollbrink,Joakim Lundeberg,David van Dijk,Jeff Holst,Leonard D Goldstein,Sarah Kummerfeld,Smita Krishnaswamy,Christine L Chaffer
{"title":"AAnet resolves a continuum of spatially-localized cell states to unveil intratumoral heterogeneity.","authors":"Aarthi Venkat,Scott E Youlten,Beatriz P San Juan,Carley A Purcell,Shabarni Gupta,Matthew Amodio,Daniel P Neumann,John G Lock,Anton E Westacott,Cerys S McCool,Daniel B Burkhardt,Andrew Benz,Annelie Mollbrink,Joakim Lundeberg,David van Dijk,Jeff Holst,Leonard D Goldstein,Sarah Kummerfeld,Smita Krishnaswamy,Christine L Chaffer","doi":"10.1158/2159-8290.cd-24-0684","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0684","url":null,"abstract":"Identifying functionally important cell states and structure within heterogeneous tumors remains a significant biological and computational challenge. Current clustering or trajectory-based models are ill-equipped to address the notion that cancer cells reside along a phenotypic continuum. We present Archetypal Analysis network (AAnet), a neural network that learns archetypal states within a phenotypic continuum in single-cell data. Unlike traditional archetypal analysis, AAnet learns archetypes in simplex-shaped neural network latent space. Using pre-clinical models and clinical breast cancers, AAnet resolves distinct cell states and processes, including cell proliferation, hypoxia, metabolism and immune interactions. Primary tumor archetypes are recapitulated in matched liver, lung and lymph node metastases. Spatial transcriptomics reveal archetypal organization within the tumor, and, intra-archetypal mirroring between cancer and adjacent stromal cells. AAnet identifies GLUT3 within the hypoxic archetype that proves critical for tumor growth and metastasis. AAnet is a powerful tool, capturing complex, functional cell states from multimodal data.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"19 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370134","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}
Cancer discoveryPub Date : 2025-06-19DOI: 10.1158/2159-8290.CD-24-1517
Shellaina J V Gordon, Florian Perner, Laura MacPherson, Katie A Fennell, Daniela V Wenge, Wallace Bourgeois, Tabea Klaus, Thomas Plenge, Anelya Murat, Jelena Petrovic, Jakub Horvath, Joan Q Cao, John D Lapek, Sean Uryu, Jeffrey R White, Enid Yn Lam, Xinmeng Jasmine Mu, Yih-Chih Chan, Andrea Gillespie, Benjamin J Blyth, Michelle A Camerino, Ylva E Bozikis, Henrietta Holze, Kathy Knezevic, Jesse Balic, Paul A Stupple, Ian P Street, Brendon J Monahan, Shikhar Sharma, Elanor N Wainwright, Dane Vassiliadis, Thomas A Paul, Scott A Armstrong, Mark A Dawson
{"title":"Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia.","authors":"Shellaina J V Gordon, Florian Perner, Laura MacPherson, Katie A Fennell, Daniela V Wenge, Wallace Bourgeois, Tabea Klaus, Thomas Plenge, Anelya Murat, Jelena Petrovic, Jakub Horvath, Joan Q Cao, John D Lapek, Sean Uryu, Jeffrey R White, Enid Yn Lam, Xinmeng Jasmine Mu, Yih-Chih Chan, Andrea Gillespie, Benjamin J Blyth, Michelle A Camerino, Ylva E Bozikis, Henrietta Holze, Kathy Knezevic, Jesse Balic, Paul A Stupple, Ian P Street, Brendon J Monahan, Shikhar Sharma, Elanor N Wainwright, Dane Vassiliadis, Thomas A Paul, Scott A Armstrong, Mark A Dawson","doi":"10.1158/2159-8290.CD-24-1517","DOIUrl":"10.1158/2159-8290.CD-24-1517","url":null,"abstract":"<p><p>Targeting the MYST acetyltransferases are an exciting therapeutic opportunity in acute myeloid leukaemia (AML). Here we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models showing that although KAT6A/B inhibition is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate oncogenic transcriptional programs. Focusing on MLL fusion oncoprotein (MLL-FP) AML, we show that inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of the MLL-FP. Combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Notably, KAT7 remains an important targetable dependency in acquired genetic/non-genetic resistance to Menin inhibition providing the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324571","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}
Cancer discoveryPub Date : 2025-06-19DOI: 10.1158/2159-8290.CD-24-1772
Nicole L Michmerhuizen, Emily B Heikamp, Ilaria Iacobucci, Masayuki Umeda, Bright Arthur, Vibhor Mishra, Chun Shik Park, Danika Di Giacomo, Ryan Hiltenbrand, Qingsong Gao, Sandi Radko-Juettner, Josi Lott, Cynthia Martucci, Varsha Subramanyam, Charlie Hatton, Daniela V Wenge, Pradyuamna Baviskar, Pablo Portola, Aurelie Claquin, Bappaditya Chandra, David W Baggett, Ali Khalighifar, Hongling Huang, Peipei Zhou, Lingyun Long, Hao Shi, Yu Sun, Evangelia K Papachristou, Chandra Sekhar Reddy Chilamakuri, Francisca N de Luna Vitorino, Joanna M Gongora, Huiyun Wu, Stanley B Pounds, Laura J Janke, Alex Kentsis, Clive S D'Santos, Benjamin A Garcia, Richard W Kriwacki, Hongbo Chi, Jeffery M Klco, Scott A Armstrong, Charles G Mullighan
{"title":"KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.","authors":"Nicole L Michmerhuizen, Emily B Heikamp, Ilaria Iacobucci, Masayuki Umeda, Bright Arthur, Vibhor Mishra, Chun Shik Park, Danika Di Giacomo, Ryan Hiltenbrand, Qingsong Gao, Sandi Radko-Juettner, Josi Lott, Cynthia Martucci, Varsha Subramanyam, Charlie Hatton, Daniela V Wenge, Pradyuamna Baviskar, Pablo Portola, Aurelie Claquin, Bappaditya Chandra, David W Baggett, Ali Khalighifar, Hongling Huang, Peipei Zhou, Lingyun Long, Hao Shi, Yu Sun, Evangelia K Papachristou, Chandra Sekhar Reddy Chilamakuri, Francisca N de Luna Vitorino, Joanna M Gongora, Huiyun Wu, Stanley B Pounds, Laura J Janke, Alex Kentsis, Clive S D'Santos, Benjamin A Garcia, Richard W Kriwacki, Hongbo Chi, Jeffery M Klco, Scott A Armstrong, Charles G Mullighan","doi":"10.1158/2159-8290.CD-24-1772","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1772","url":null,"abstract":"<p><p>NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML). NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell-associated genes in cooperation with epigenetic regulators. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including KAT6A/MOZ, KAT7/HBO1, and the common KAT6A/7 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of Kat6a and Kat7 impairs NUP98-r cell fitness. KAT6A/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r AML.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324572","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}
Cancer discoveryPub Date : 2025-06-18DOI: 10.1158/2159-8290.cd-24-1208
Joanna Pozniak, Niccolò Roda, Ewout Landeloos, Asier Antoranz, Yannick Van Herck, Amber De Visscher, Philip Georg Demaerel, Lukas Vanwynsberghe, Jeroen Declercq, Christos Gkemisis, Greet Bervoets, No-Joon Song, Ayse Bassez, Robin Browaeys, Lotte Pollaris, Francesca M. Bosisio, Veerle Boecxstaens, Yvan Saeys, Diether Lambrechts, Zihai Li, Patrick Matthys, Oliver Bechter, Jean-Christophe Marine
{"title":"Cytotoxic NK Cells Impede Response to Checkpoint Immunotherapy in Melanoma with an Immune-Excluded Phenotype","authors":"Joanna Pozniak, Niccolò Roda, Ewout Landeloos, Asier Antoranz, Yannick Van Herck, Amber De Visscher, Philip Georg Demaerel, Lukas Vanwynsberghe, Jeroen Declercq, Christos Gkemisis, Greet Bervoets, No-Joon Song, Ayse Bassez, Robin Browaeys, Lotte Pollaris, Francesca M. Bosisio, Veerle Boecxstaens, Yvan Saeys, Diether Lambrechts, Zihai Li, Patrick Matthys, Oliver Bechter, Jean-Christophe Marine","doi":"10.1158/2159-8290.cd-24-1208","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1208","url":null,"abstract":"Immune checkpoint blockade (ICB) has revolutionized cancer treatment. Unfortunately, the inability of lymphocytes to infiltrate the tumor nest, a phenomenon known as immune exclusion, drastically limits ICB responsiveness. Analyzing the immune landscape of matched pre- and early on-treatment biopsies of patients with melanoma undergoing ICB therapy, we observed a significant increase in cytotoxic NK cells in early on-treatment biopsies from nonresponders. Spatial multiomic analyses revealed that, although NK cells colocalized with CD8+ T cells within the tumor bed in responding lesions, they were excluded from the tumor parenchyma in nonresponding lesions. Strikingly, pharmacologic depletion of NK cells in a unique melanoma mouse model exhibiting an immune-excluded phenotype unleashed immune infiltration of the tumor core and tumor clearance upon ICB exposure. Mechanistically, we show that NK cells are actively recruited to immune-excluded areas upon ICB exposure via the chemokine receptor CX3CR1 to suppress tumor infiltration and antitumor function of CD8+ T cells. Significance: Immune exclusion is responsible for intrinsic resistance to ICB in about half of nonresponder patients. Our unexpected observation that targeting NK cell biology unleashes the recruitment and antitumor activity of CD8+ T cells in tumors with an immune-excluded phenotype offers a potential therapeutic avenue for this large patient population. See related article by Song et al., p. XX","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320096","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}
Cancer discoveryPub Date : 2025-06-18DOI: 10.1158/2159-8290.cd-24-1232
No-Joon Song, Juan Xie, Kyeong Joo Jung, Yi Wang, Joanna Pozniak, Niccolo Roda, Jean-Christophe Marine, Brian P. Riesenberg, Hyeongseon Jeon, Anjun Ma, Nathanael Cox, Darren Wethington, Kelsi Reynolds, Tong Xiao, Anqi Li, Parker Kronen, Nicholas Denko, David P. Carbone, Qin Ma, William E. Carson, Bethany L. Mundy-Bosse, Christin E. Burd, Jayajit Das, Dongjun Chung, Zihai Li
{"title":"Tumor-Associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers","authors":"No-Joon Song, Juan Xie, Kyeong Joo Jung, Yi Wang, Joanna Pozniak, Niccolo Roda, Jean-Christophe Marine, Brian P. Riesenberg, Hyeongseon Jeon, Anjun Ma, Nathanael Cox, Darren Wethington, Kelsi Reynolds, Tong Xiao, Anqi Li, Parker Kronen, Nicholas Denko, David P. Carbone, Qin Ma, William E. Carson, Bethany L. Mundy-Bosse, Christin E. Burd, Jayajit Das, Dongjun Chung, Zihai Li","doi":"10.1158/2159-8290.cd-24-1232","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1232","url":null,"abstract":"Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis represent established therapies for many cancers. However, resistance occurs in most patients due to complex immune-suppressive mechanisms in the tumor microenvironment. NK cells can play effector roles in tumor control, but their impact on T-cell dysfunction and ICB efficacy remains controversial. Through genetic and antibody-mediated NK cell depletion, we found that a subset of tumor-associated NK cells plays a negative role in ICB sensitivity; they further impede CD8+ T-cell differentiation toward a CD69+ BCL2+ EOMES+ GZMB+ TIM3− GITR− phenotype. Mechanistically, the retinoic acid receptor α–dependent differentiation program in CD8+ T cells is hindered by tumor-infiltrating NK cells via competition for IFNα and IL-2. Finally, we observed that lower frequencies of NK cells correlate with better clinical responses to ICBs in patients with cancer. These findings suggest potential avenues for enhancing CD8+ T cell–centered immunotherapy by targeting regulatory NK cells. Significance: Although NK cells are traditionally viewed as antitumor effectors, our study uncovers their unexpected suppressive role in CD8+ T cell–based immunotherapy. By competing for cytokines, they disrupt retinoic acid receptor α–driven CD8+ T-cell differentiation and limit ICB efficacy. Clinically, reduced NK cell presence is associated with an enhanced immunotherapy response. See related article by Pozniak et al. p. XX","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"13 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319741","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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