Nature cancerPub Date : 2025-04-03DOI: 10.1038/s43018-025-00935-0
Liuling Xiao, Rui Duan, Wendao Liu, Chuanchao Zhang, Xingzhe Ma, Miao Xian, Qiang Wang, Qi Guo, Wei Xiong, Pan Su, Lingqun Ye, Yabo Li, Ling Zhong, Jianfei Qian, Yong Lu, Zhongming Zhao, Qing Yi
{"title":"Adoptively transferred tumor-specific IL-9-producing cytotoxic CD8<sup>+</sup> T cells activate host CD4<sup>+</sup> T cells to control tumors with antigen loss.","authors":"Liuling Xiao, Rui Duan, Wendao Liu, Chuanchao Zhang, Xingzhe Ma, Miao Xian, Qiang Wang, Qi Guo, Wei Xiong, Pan Su, Lingqun Ye, Yabo Li, Ling Zhong, Jianfei Qian, Yong Lu, Zhongming Zhao, Qing Yi","doi":"10.1038/s43018-025-00935-0","DOIUrl":"https://doi.org/10.1038/s43018-025-00935-0","url":null,"abstract":"<p><p>Host effector CD4<sup>+</sup> T cells emerge as critical mediators for tumor regression but whether they can be activated by adoptively transferred CD8<sup>+</sup> T cells remains unknown. We previously reported that adoptive transfer of interleukin 9 (IL-9)-producing cytotoxic CD8<sup>+</sup> T (Tc9) cells achieved long-term control of tumor growth. Here, we demonstrate that murine tumor-specific Tc9 cells control the outgrowth of antigen-loss relapsed tumors by recruiting and activating host effector CD4<sup>+</sup> T cells. Tc9 cells secreted IL-24 and recruited CCR7-expressing conventional type 2 dendritic cells (cDC2 cells) into tumor-draining lymph nodes to prime host CD4<sup>+</sup> T cells against relapsed tumors. Host CD4<sup>+</sup> T cell or cDC2 deficiency impaired the ability of Tc9 cells to control relapsed tumor outgrowth. Additionally, intratumoral IL24 expression correlates with cDC2 and CD4<sup>+</sup> T cell gene signatures in human cancers and their expression is associated with better patient survival. This study reports a mechanism for activation of tumor-specific CD4<sup>+</sup> T cells in vivo.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780565","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 : 2025-04-03DOI: 10.1038/s43018-025-00941-2
Guillaume Cartron, Roch Houot, Yassine Al Tabaa, Fabien Le Bras, Loïc Ysebaert, Sylvain Choquet, Fabrice Jardin, Jacques-Olivier Bay, François-Xavier Gros, Franck Morschhauser, Olivier Casasnovas, Thomas Gastinne, Catherine Thieblemont, Magalie Joris, Laure Ricard, Caroline Regny, Laurianne Drieu La Rochelle, Pierre Feugier, Ambroise Marcais, Samuel Griolet, Karin Tarte, Camille Laurent, Pierre Sesques
{"title":"Glofitamab in refractory or relapsed diffuse large B cell lymphoma after failing CAR-T cell therapy: a phase 2 LYSA study.","authors":"Guillaume Cartron, Roch Houot, Yassine Al Tabaa, Fabien Le Bras, Loïc Ysebaert, Sylvain Choquet, Fabrice Jardin, Jacques-Olivier Bay, François-Xavier Gros, Franck Morschhauser, Olivier Casasnovas, Thomas Gastinne, Catherine Thieblemont, Magalie Joris, Laure Ricard, Caroline Regny, Laurianne Drieu La Rochelle, Pierre Feugier, Ambroise Marcais, Samuel Griolet, Karin Tarte, Camille Laurent, Pierre Sesques","doi":"10.1038/s43018-025-00941-2","DOIUrl":"https://doi.org/10.1038/s43018-025-00941-2","url":null,"abstract":"<p><p>Persons with diffuse large B cell lymphoma (DLBCL) refractory or in first progression/relapsed (R/R) after chimeric antigen receptor T (CAR-T) cell therapy exhibit dramatic outcomes. We enrolled such persons in a phase 2 single-arm, nonblinded trial ( NCT04703686 ) to evaluate the efficacy and safety of glofitamab, a CD20-CD3 T cell-engaging bispecific antibody, using a short ramp-up regimen to reach full dose within 1 week. A total of 46 participants received at least one glofitamab infusion following obinutuzumab (anti-CD20 monoclonal antibody) pretreatment. The primary endpoint was overall survival (OS). Secondary endpoints included independent-assessed best overall metabolic response rate (OMRR) and complete metabolic response rate (CMRR), progression-free survival (PFS), duration of response, safety and tolerability and health-related quality of life. After a median follow-up of 15.3 months (95% confidence interval (CI), 10.1-17.7), the primary endpoint was met, achieving a median OS of 14.7 months (90% CI, 8.8-not reached). The best OMRR was 76.1%. The best CMRR was 45.7%. The median PFS was 3.8 months (95% CI, 2.4-19.6). Despite the shortened setup dosing, no excess cytokine release syndrome or neurotoxicity events were observed (grade ≥ 3, 0% for both). In conclusion, glofitamab improved OS in participants with R/R DLBCL after CAR-T cell therapy, with a favorable safety profile.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780632","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 : 2025-03-31DOI: 10.1038/s43018-025-00931-4
{"title":"Near-infrared optogenetic engineering of bacteria for cancer therapy.","authors":"","doi":"10.1038/s43018-025-00931-4","DOIUrl":"https://doi.org/10.1038/s43018-025-00931-4","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753543","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 : 2025-03-28DOI: 10.1038/s43018-025-00929-y
Xavier Catena, Marta Contreras-Alcalde, Naiara Juan-Larrea, Daniela Cerezo-Wallis, Tonantzin G Calvo, Cynthia Mucientes, David Olmeda, Javier Suárez, Sergio Oterino-Sogo, Lola Martínez, Diego Megías, David Sancho, Cristina Tejedo, Susana Frago, Diana Dudziak, Athanasios Seretis, Patrizia Stoitzner, María S Soengas
{"title":"Systemic rewiring of dendritic cells by melanoma-secreted midkine impairs immune surveillance and response to immune checkpoint blockade.","authors":"Xavier Catena, Marta Contreras-Alcalde, Naiara Juan-Larrea, Daniela Cerezo-Wallis, Tonantzin G Calvo, Cynthia Mucientes, David Olmeda, Javier Suárez, Sergio Oterino-Sogo, Lola Martínez, Diego Megías, David Sancho, Cristina Tejedo, Susana Frago, Diana Dudziak, Athanasios Seretis, Patrizia Stoitzner, María S Soengas","doi":"10.1038/s43018-025-00929-y","DOIUrl":"https://doi.org/10.1038/s43018-025-00929-y","url":null,"abstract":"<p><p>Cutaneous melanomas express a high number of potential neoepitopes, yet a substantial fraction of melanomas shift into immunologically cold phenotypes. Using cellular systems, mouse models and large datasets, we identify the tumor-secreted growth factor midkine (MDK) as a multilayered inhibitor of antigen-presenting cells. Mechanistically, MDK acts systemically in primary tumors, lymph nodes and the bone marrow, promoting a STAT3-mediated impairment of differentiation, activation and function of dendritic cells (DCs), particularly, conventional type 1 DCs (cDC1s). Furthermore, MDK rewires DCs toward a tolerogenic state, impairing CD8<sup>+</sup> T cell activation. Downregulating MDK improves DC-targeted vaccination, CD40 agonist treatment and immune checkpoint blockade in mouse models. Moreover, we present an MDK-associated signature in DCs that defines poor prognosis and immune checkpoint blockade resistance in individuals with cancer. An inverse correlation between MDK- and cDC1-associated signatures was observed in a variety of tumor types, broadening the therapeutic implications of MDK in immune-refractory malignancies.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742922","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":"CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant.","authors":"Shunya Ikeda, Kana Hasegawa, Yosuke Kogue, Takao Arimori, Ryuhei Kawamoto, Tansri Wibowo, Moto Yaga, Yuri Inada, Hirofumi Uehara, Miwa Matsubara, Mana Tachikawa, Makiko Suga, Shuhei Kida, Kumi Shibata, Kazuhito Tsutsumi, Kentaro Fukushima, Jiro Fujita, Tomoaki Ueda, Shinsuke Kusakabe, Akihisa Hino, Michiko Ichii, Asao Hirose, Hirohisa Nakamae, Masayuki Hino, Takafumi Nakao, Megumu Inoue, Kyoko Yoshihara, Satoshi Yoshihara, Shuji Ueda, Tetsuro Tachi, Hideki Kuroda, Koki Murakami, Noriyuki Kijima, Haruhiko Kishima, Eri Igashira, Mari Murakami, Tsuyoshi Takiuchi, Tadashi Kimura, Takashi Hiroshima, Toru Kimura, Yasushi Shintani, Chihaya Imai, Kosuke Yusa, Ryota Mori, Takayuki Ogino, Hidetoshi Eguchi, Kiyoshi Takeda, Yusuke Oji, Atsushi Kumanogoh, Junichi Takagi, Naoki Hosen","doi":"10.1038/s43018-025-00934-1","DOIUrl":"https://doi.org/10.1038/s43018-025-00934-1","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML)-specific target antigens are difficult to identify. Here we demonstrate that HLA-DRB1 can serve as a leukemia-specific target of chimeric antigen receptor (CAR) T cells in patients with AML after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified KG2032 as a monoclonal antibody specifically bound to AML cells in about half of patients, but not to normal leukocytes other than B lymphocytes. KG2032 reacted with a subset of HLA-DRB1 molecules, specifically those in which the 86th amino acid was not aspartic acid. KG2032 reacted minimally with nonhematopoietic tissues. These results indicate that KG2032 reactivity is highly specific for AML cells in patients who carry KG2032-reactive HLA-DRB1 alleles and who received allo-HCT from a donor carrying KG2032-nonreactive HLA-DRB1 alleles. KG2032-derived CAR T or natural killer cells showed significant anti-leukemic activity in preclinical models in female mice, suggesting that they may cure patients with AML who are incurable with allo-HCT.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701090","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 : 2025-03-19DOI: 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":"https://doi.org/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":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-19","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}
{"title":"Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer.","authors":"Hanling Wang, Sulin Zhang, Qiang Pan, Jiacheng Guo, Ni Li, Lifan Chen, Junyu Xu, Jingyi Zhou, Yongqiang Gu, Xuege Wang, Guoying Zhang, Yannan Lian, Wei Zhang, Naiheng Lin, Zige Jin, Yi Zang, Weihua Lan, Xiaoyan Cheng, Minjia Tan, Fei Xavier Chen, Jun Jiang, Qiuli Liu, Mingyue Zheng, Jun Qin","doi":"10.1038/s43018-025-00928-z","DOIUrl":"https://doi.org/10.1038/s43018-025-00928-z","url":null,"abstract":"<p><p>The transdifferentiation from adenocarcinoma to neuroendocrine prostate cancer (NEPC) in men confers antiandrogen therapy resistance. Here our analysis combining CRISPR‒Cas9 screening with single-cell RNA sequencing tracking of tumor transition demonstrated that antiandrogen-induced zinc finger MYND-type containing 8 (ZMYND8)-dependent epigenetic programming orchestrates NEPC transdifferentiation. Ablation of Zmynd8 prevents NEPC development, while ZMYND8 upregulation mediated by achaete-scute homolog 1 promotes NEPC differentiation. We show that forkhead box protein M1 (FOXM1) stabilizes ZMYND8 binding to chromatin regions characterized by H3K4me1-H3K14ac modification and FOXM1 targeting. Antiandrogen therapy releases the SWI/SNF chromatin remodeling complex from the androgen receptor, facilitating its interaction with ZMYND8-FOXM1 to upregulate critical neuroendocrine lineage regulators. We develop iZMYND8-34, a small molecule designed to inhibit ZMYND8's histone recognition, which effectively blocks NEPC development. These findings reveal the critical role of ZMYND8-dependent epigenetic programming induced by androgen deprivation therapy in orchestrating lineage fate. Targeting ZMYND8 emerges as a promising strategy for impeding NEPC development.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657808","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 : 2025-03-18DOI: 10.1038/s43018-025-00906-5
Kate E Dunmore, David S Rickman
{"title":"Targeting anti-androgen therapy resistance through epigenetic rewiring.","authors":"Kate E Dunmore, David S Rickman","doi":"10.1038/s43018-025-00906-5","DOIUrl":"https://doi.org/10.1038/s43018-025-00906-5","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657807","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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