Nature cancerPub Date : 2025-05-22DOI: 10.1038/s43018-025-00979-2
Anca Apavaloaei, Qingchuan Zhao, Leslie Hesnard, Maxime Cahuzac, Chantal Durette, Jean-David Larouche, Marie-Pierre Hardy, Krystel Vincent, Sylvie Brochu, Jean-Philippe Laverdure, Joël Lanoix, Mathieu Courcelles, Patrick Gendron, Mathieu Lajoie, Maria Virginia Ruiz Cuevas, Eralda Kina, Julie Perrault, Juliette Humeau, Grégory Ehx, Sébastien Lemieux, Ian R Watson, Daniel E Speiser, Michal Bassani-Sternberg, Pierre Thibault, Claude Perreault
{"title":"Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer.","authors":"Anca Apavaloaei, Qingchuan Zhao, Leslie Hesnard, Maxime Cahuzac, Chantal Durette, Jean-David Larouche, Marie-Pierre Hardy, Krystel Vincent, Sylvie Brochu, Jean-Philippe Laverdure, Joël Lanoix, Mathieu Courcelles, Patrick Gendron, Mathieu Lajoie, Maria Virginia Ruiz Cuevas, Eralda Kina, Julie Perrault, Juliette Humeau, Grégory Ehx, Sébastien Lemieux, Ian R Watson, Daniel E Speiser, Michal Bassani-Sternberg, Pierre Thibault, Claude Perreault","doi":"10.1038/s43018-025-00979-2","DOIUrl":"https://doi.org/10.1038/s43018-025-00979-2","url":null,"abstract":"<p><p>Melanoma and non-small cell lung cancer (NSCLC) display exceptionally high mutational burdens. Hence, immune targeting in these cancers has primarily focused on tumor antigens (TAs) predicted to derive from nonsynonymous mutations. Using comprehensive proteogenomic analyses, we identified 589 TAs in cutaneous melanoma (n = 505) and NSCLC (n = 90). Of these, only 1% were derived from mutated sequences, which was explained by a low RNA expression of most nonsynonymous mutations and their localization outside genomic regions proficient for major histocompatibility complex (MHC) class I-associated peptide generation. By contrast, 99% of TAs originated from unmutated genomic sequences specific to cancer (aberrantly expressed tumor-specific antigens (aeTSAs), n = 220), overexpressed in cancer (tumor-associated antigens (TAAs), n = 165) or specific to the cell lineage of origin (lineage-specific antigens (LSAs), n = 198). Expression of aeTSAs was epigenetically regulated, and most were encoded by noncanonical genomic sequences. aeTSAs were shared among tumor samples, were immunogenic and could contribute to the response to immune checkpoint blockade observed in previous studies, supporting their immune targeting across cancers.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128216","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 : 2025-05-20DOI: 10.1038/s43018-025-00982-7
Helen Carrasco Hope, Jana de Sostoa, Pierpaolo Ginefra, Massimo Andreatta, Yi-Hsuan Chiang, Catherine Ronet, Christine Pich-Bavastro, Jesús Corria Osorio, François Kuonen, Johan Auwerx, Patrizia D'Amelio, Ping-Chih Ho, Santiago J Carmona, George Coukos, Denis Migliorini, Nicola Vannini
{"title":"Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.","authors":"Helen Carrasco Hope, Jana de Sostoa, Pierpaolo Ginefra, Massimo Andreatta, Yi-Hsuan Chiang, Catherine Ronet, Christine Pich-Bavastro, Jesús Corria Osorio, François Kuonen, Johan Auwerx, Patrizia D'Amelio, Ping-Chih Ho, Santiago J Carmona, George Coukos, Denis Migliorini, Nicola Vannini","doi":"10.1038/s43018-025-00982-7","DOIUrl":"10.1038/s43018-025-00982-7","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111200","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":"Safety and feasibility of 4-1BB co-stimulated CD19-specific CAR-NK cell therapy in refractory/relapsed large B cell lymphoma: a phase 1 trial.","authors":"Wen Lei, Hui Liu, Wenhai Deng, Wei Chen, Yun Liang, Wenxia Gao, Xianggui Yuan, Shanshan Guo, Ping Li, Jinyong Wang, Xiangmin Tong, Yi Eve Sun, Aibin Liang, Wenbin Qian","doi":"10.1038/s43018-025-00940-3","DOIUrl":"10.1038/s43018-025-00940-3","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-modified NK (CAR-NK) cells are candidates for next-generation cancer immunotherapies. Here we generated CD19-specific CAR-NK cells with 4-1BB and CD3ζ signaling endo-domains (CD19-BBz CAR-NK) by transduction of cord blood-derived NK cells using baboon envelope pseudotyped lentiviral vectors and demonstrated their antitumor activity in preclinical B cell lymphoma models in female mice. We next conducted a phase 1 dose-escalation trial involving repetitive administration of CAR-NK cells in 8 patients with relapsed/refractory large B cell lymphoma (NCT05472558). Primary end points were safety, maximum tolerated dose, and overall response rate. Secondary end points included duration of response, overall survival, and progression-free survival. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. No cases of cytokine release syndrome, neurotoxicity, or graft-versus-host disease were observed. Results showed an overall response rate of 62.5% at day 30, with 4 patients (50%) achieving complete response. The median progression-free survival was 9.5 months, and the median overall survival was not reached. A post hoc exploratory single-cell RNA sequencing analysis revealed molecular features of CAR-NK cells associated with therapeutic efficacy and efficacy-related immune cell interaction networks. This study met the pre-specified end points. In conclusion, CD19-BBz CAR-NK cells were feasible and therapeutically safe, capable of inducing durable response in patients with B cell lymphoma.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"786-800"},"PeriodicalIF":23.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004875","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":"An organoid library unveils subtype-specific IGF-1 dependency via a YAP-AP1 axis in human small cell lung cancer.","authors":"Takahiro Fukushima, Kazuhiro Togasaki, Junko Hamamoto, Katsura Emoto, Toshiki Ebisudani, Akifumi Mitsuishi, Kai Sugihara, Taro Shinozaki, Masahiko Okada, Ayaka Saito, Hatsuyo Takaoka, Fumimaro Ito, Lisa Shigematsu, Yuki Ohta, Sirirat Takahashi, Mami Matano, Yutaka Kurebayashi, Keiko Ohgino, Takashi Sato, Ichiro Kawada, Keisuke Asakura, Tomoyuki Hishida, Hisao Asamura, Shinnosuke Ikemura, Hideki Terai, Kenzo Soejima, Mayumi Oda, Masayuki Fujii, Koichi Fukunaga, Hiroyuki Yasuda, Toshiro Sato","doi":"10.1038/s43018-025-00945-y","DOIUrl":"10.1038/s43018-025-00945-y","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is a devastating disease with limited therapeutic advancements. Although SCLC has recently been classified into four molecular subtypes, subtype-specific therapies are still lacking. Here, we established 40 patient-derived SCLC organoid lines with predominant TP53 and RB1 alterations and rare targetable genetic lesions. Transcriptome profiling divided the SCLC organoids into neuroendocrine (NE)-type SCLC and non-NE-type SCLC, with the latter characterized by YAP1 or POU2F3 expression. NE-type SCLC organoids grew independent of alveolar niche factors, whereas non-NE-type SCLC organoids relied on insulin-like growth factor (IGF)-1-driven YAP1 and AP1 activation. Therapeutic targeting of IGF-1, YAP1 and AP1 effectively suppressed the growth of non-NE-type organoids. Co-knockout of TP53 and RB1 in human alveolar cells altered their lineage toward the airway epithelium-like fate and conferred IGF-1 dependency, validating the subtype-phenotype connection. Our SCLC organoid library represents a valuable resource for developing biology-based therapies and has the potential to reshape the drug discovery landscape.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"874-891"},"PeriodicalIF":23.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019215","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 : 2025-05-01DOI: 10.1038/s43018-025-00967-6
Won Seog Kim, Tae Min Kim, Seok-Goo Cho, Isidro Jarque, Elżbieta Iskierka-Jażdżewska, Li Mei Poon, H Miles Prince, Huilai Zhang, Junning Cao, Mingzhi Zhang, Benoît Tessoulin, Sung Yong Oh, Francesca Lim, Cecilia Carpio, Tran-Der Tan, Sabarish Ayyappan, Antonio Gutierrez, Jingxian Cai, Melanie Ufkin, Saleem Shariff, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Srikanth Ambati, Jan Walewski
{"title":"Author Correction: Odronextamab monotherapy in patients with relapsed/refractory diffuse large B cell lymphoma: primary efficacy and safety analysis in phase 2 ELM-2 trial.","authors":"Won Seog Kim, Tae Min Kim, Seok-Goo Cho, Isidro Jarque, Elżbieta Iskierka-Jażdżewska, Li Mei Poon, H Miles Prince, Huilai Zhang, Junning Cao, Mingzhi Zhang, Benoît Tessoulin, Sung Yong Oh, Francesca Lim, Cecilia Carpio, Tran-Der Tan, Sabarish Ayyappan, Antonio Gutierrez, Jingxian Cai, Melanie Ufkin, Saleem Shariff, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Srikanth Ambati, Jan Walewski","doi":"10.1038/s43018-025-00967-6","DOIUrl":"10.1038/s43018-025-00967-6","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"907"},"PeriodicalIF":23.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12122359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018461","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":"PILRα on tumor cells interacts with the T cell surface protein CD99 to suppress antitumor immunity.","authors":"Lin Xia, Jun-Yi Liu, Chao Yu, Hong-Wei Lin, Ya-Hong Hu, Guo-Sheng Hu, Yao-Hui He, Yun-Yao Chen, Wen-Xin Luo, Ning-Shao Xia, Wen Liu","doi":"10.1038/s43018-025-00958-7","DOIUrl":"https://doi.org/10.1038/s43018-025-00958-7","url":null,"abstract":"<p><p>Immune checkpoint blockade using anti-programmed cell death protein 1/programmed cell death 1 ligand 1 antibody effectively targets the tumor-T cell interaction in cancer treatment, yet the overall response rate of less than 30% necessitates the identification of additional immune checkpoints modulating T cell function. Here, we identified the tumor cell-expressed paired immunoglobulin-like type 2 receptor alpha (PILRα) as an immune suppressor targeting T cells using high-throughput screening. PILRα inhibits T cell activation, proliferation and effector function by targeting CD99, a T cell surface antigen, suppressing ZAP70/NFAT/IL-2/JAK/STAT signaling. A cluster of O-glycosylated serine and threonine residues within the stalk region is critical for PILRα-CD99 interactions. Blocking these interactions with a stalk-targeting anti-PILRα antibody enhances T cell antitumor immunity and suppresses tumor growth. When combined with programmed cell death protein 1 antibody, anti-PILRα antibody shows synergistic tumor suppression. Notably, PILRα is highly expressed in several human cancers and predicts poor prognosis. These findings unveil PILRα as an immune checkpoint with therapeutic potential for clinical cancer immunotherapy.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044849","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 : 2025-05-01DOI: 10.1038/s43018-025-00995-2
Luca Danelli
{"title":"Sex-specific gut microbiota and neutrophil senescence in bladder cancer.","authors":"Luca Danelli","doi":"10.1038/s43018-025-00995-2","DOIUrl":"10.1038/s43018-025-00995-2","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"738"},"PeriodicalIF":23.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132684","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 : 2025-05-01Epub Date: 2025-03-19DOI: 10.1038/s43018-025-00937-y
Liang Zhou, Guangyu Lian, Tao Zhou, Zhe Cai, Shuai Yang, Weining Li, Lilin Cheng, Ying Ye, Mingfeng He, Jianru Lu, Qifeng Deng, Bihui Huang, Xiaoqian Zhou, Desheng Lu, Feng Zhi, Jun Cui
{"title":"Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity.","authors":"Liang Zhou, Guangyu Lian, Tao Zhou, Zhe Cai, Shuai Yang, Weining Li, Lilin Cheng, Ying Ye, Mingfeng He, Jianru Lu, Qifeng Deng, Bihui Huang, Xiaoqian Zhou, Desheng Lu, Feng Zhi, Jun Cui","doi":"10.1038/s43018-025-00937-y","DOIUrl":"10.1038/s43018-025-00937-y","url":null,"abstract":"<p><p>Ferroptosis is closely linked with various pathophysiological processes, including aging, neurodegeneration, ischemia-reperfusion injury, viral infection and, notably, cancer progression; however, its post-translational regulatory mechanisms remain incompletely understood. Here we revealed a crucial role of S-palmitoylation in regulating ferroptosis through glutathione peroxidase 4 (GPX4), a pivotal enzyme that mitigates lipid peroxidation. We identified that zinc finger DHHC-domain containing protein 8 (zDHHC8), an S-acyltransferase that is highly expressed in multiple tumors, palmitoylates GPX4 at Cys75. Through small-molecule drug screening, we identified PF-670462, a zDHHC8-specific inhibitor that promotes the degradation of zDHHC8, consequently attenuating GPX4 palmitoylation and enhancing ferroptosis sensitivity. PF-670462 inhibition of zDHHC8 facilitates the CD8<sup>+</sup> cytotoxic T cell-induced ferroptosis of tumor cells, thereby improving the efficacy of cancer immunotherapy in a B16-F10 xenograft model. Our findings reveal the prominent role of the zDHHC8-GPX4 axis in regulating ferroptosis and highlight the potential application of zDHHC8 inhibitors in anticancer therapy.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"768-785"},"PeriodicalIF":23.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663926","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 : 2025-05-01Epub Date: 2025-05-08DOI: 10.1038/s43018-025-00946-x
Chao Wang, Xiaoqing Yu, Jamie K Teer, Jiqiang Yao, Dongliang Du, Xiaoxian Liu, Zachary J Thompson, Min Hsuan Wang, Eric A Welsh, Danish Memon, Timothy A Chan, Vladimir Makarov, Carmen M Anadon, Lamees Saeed, Theresa A Boyle, Bin Fang, John M Koomen, Cheryl Cox, Ana M Landin, Sean J Yoder, Sungjune Kim, Dung-Tsa Chen, Shari A Pilon-Thomas, Jose R Conejo-Garcia, Scott J Antonia, Eric B Haura, Benjamin C Creelan
{"title":"Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy.","authors":"Chao Wang, Xiaoqing Yu, Jamie K Teer, Jiqiang Yao, Dongliang Du, Xiaoxian Liu, Zachary J Thompson, Min Hsuan Wang, Eric A Welsh, Danish Memon, Timothy A Chan, Vladimir Makarov, Carmen M Anadon, Lamees Saeed, Theresa A Boyle, Bin Fang, John M Koomen, Cheryl Cox, Ana M Landin, Sean J Yoder, Sungjune Kim, Dung-Tsa Chen, Shari A Pilon-Thomas, Jose R Conejo-Garcia, Scott J Antonia, Eric B Haura, Benjamin C Creelan","doi":"10.1038/s43018-025-00946-x","DOIUrl":"10.1038/s43018-025-00946-x","url":null,"abstract":"<p><p>Cell therapy with tumor-infiltrating lymphocytes (TILs) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multidimensional analysis was performed on time-serial tumor and blood in a lung cancer TIL therapy trial. Using T cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen-specific T cell receptors. We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":"801-819"},"PeriodicalIF":23.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010080","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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