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}
Nature cancerPub Date : 2025-03-17DOI: 10.1038/s43018-025-00932-3
Longliang Qiao, Lingxue Niu, Zhihao Wang, Zhenqiang Deng, Dai Di, Xiaoding Ma, Yang Zhou, Deqiang Kong, Qilin Wang, Jianli Yin, Lingli Jin, Jing Sun, Bo Feng, Weiqiang Lu, Fengfeng Cai, Ningzi Guan, Haifeng Ye
{"title":"Engineered bacteria for near-infrared light-inducible expression of cancer therapeutics.","authors":"Longliang Qiao, Lingxue Niu, Zhihao Wang, Zhenqiang Deng, Dai Di, Xiaoding Ma, Yang Zhou, Deqiang Kong, Qilin Wang, Jianli Yin, Lingli Jin, Jing Sun, Bo Feng, Weiqiang Lu, Fengfeng Cai, Ningzi Guan, Haifeng Ye","doi":"10.1038/s43018-025-00932-3","DOIUrl":"https://doi.org/10.1038/s43018-025-00932-3","url":null,"abstract":"<p><p>Bacteria-based therapies hold great promise for cancer treatment due to their selective tumor colonization and proliferation. However, clinical application is hindered by the need for safe, precise control systems to regulate local therapeutic payload expression and release. Here we developed a near-infrared (NIR) light-mediated PadC-based photoswitch (NETMAP) system based on a chimeric phytochrome-activated diguanylyl cyclase (PadC) and a cyclic diguanylate monophosphate-dependent transcriptional activator (MrkH). The NETMAP-engineered bacteria exhibited antitumor performance in mouse tumor models with different levels of immunogenicity. Specifically, in immunogenic lymphoma tumors, NIR-induced PD-L1 and CTLA-4 nanobodies enhanced the activation of adaptive immunity. In low-immunogenic tumors-including mouse-derived colon cancer models, an orthotopic human breast cancer cell line-derived xenograft model and a colorectal cancer patient-derived xenograft model-NIR-induced azurin and cytolysin A predominantly led to tumor inhibition. Our study identifies an NIR light-mediated therapeutic platform for engineered bacteria-based therapies with customizable outputs and precise dosage control.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649730","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 : 2025-03-17DOI: 10.1038/s43018-025-00921-6
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":"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/s43018-025-00921-6","DOIUrl":"https://doi.org/10.1038/s43018-025-00921-6","url":null,"abstract":"<p><p>The phase 2, multicohort, ongoing ELM-2 study evaluates odronextamab, a CD20×CD3 bispecific antibody, in patients with relapsed/refractory (R/R) B cell non-Hodgkin lymphoma after ≥2 lines of therapy. Here primary analysis of the diffuse large B cell lymphoma (DLBCL) cohort is reported. Patients received intravenous odronextamab in 21-day cycles until progression or unacceptable toxicity, with cycle 1 step-up dosing to mitigate cytokine release syndrome (CRS) risk. The primary endpoint was objective response rate (ORR). Secondary endpoints included complete response (CR) rate, duration of response, progression-free survival (PFS) and overall survival. A total of 127 patients were enrolled. At the 29.9-month efficacy follow-up, the ORR was 52.0% and CR rate was 31.5%. Median durations of response and CR were 10.2 and 17.9 months, respectively. Undetectable minimal residual disease at cycle 4 day 15 was associated with PFS benefit. With a step-up of 0.7 to 4 to 20 mg (n = 60), CRS was the most common treatment-emergent adverse event (53.3% (grade ≥3, 1.7%)). No immune effector cell-associated neurotoxicity syndrome was reported. Infections were reported in 82/127 (64.6%) patients (grade ≥3, 38.6%; coronavirus disease 2019, 18.1% (grade ≥3, 12.6%)). In conclusion, odronextamab showed encouraging efficacy in heavily pretreated R/R DLBCL and generally manageable safety with supportive care. Clinical trial registration: NCT03888105 .</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649658","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 : 2025-03-17DOI: 10.1038/s43018-025-00927-0
Sylvain Simon, Grace Bugos, Rachel Prins, Anusha Rajan, Arulmozhi Palani, Kersten Heyer, Andrew Stevens, Longhui Zeng, Kirsten A Thompson, Pinar A Atilla, Jason P Price, Mitchell G Kluesner, Carla A Jaeger-Ruckstuhl, Tamer B Shabaneh, James M Olson, Xiaolei Su, Stanley R Riddell
{"title":"Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy.","authors":"Sylvain Simon, Grace Bugos, Rachel Prins, Anusha Rajan, Arulmozhi Palani, Kersten Heyer, Andrew Stevens, Longhui Zeng, Kirsten A Thompson, Pinar A Atilla, Jason P Price, Mitchell G Kluesner, Carla A Jaeger-Ruckstuhl, Tamer B Shabaneh, James M Olson, Xiaolei Su, Stanley R Riddell","doi":"10.1038/s43018-025-00927-0","DOIUrl":"https://doi.org/10.1038/s43018-025-00927-0","url":null,"abstract":"<p><p>The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is effective in B cell malignancies. However, the persistence of cancer cells with low levels or complete absence of the target antigen, thereby evading detection by CAR T cells, leads to relapse. These evasion mechanisms highlight the need for receptors with enhanced sensitivity and multispecificity. We introduce a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity compared with CARS and previous hybrid TCR designs and is readily adapted for bispecific targeting. ChTCRs replicate the structure of natural TCRs, form classical immune synapses and demonstrate TCR-like signaling. T cells expressing bispecific ChTCRs (Bi-ChTCRs) are more effective than bispecific CAR T cells in eradicating tumors with heterogeneous antigen expression in vivo in female mice. The Bi-ChTCR architecture is resilient and can be designed to target pairs of B cell and multiple myeloma antigens. These findings provide a widely applicable strategy to combat tumor heterogeneity and prevent relapse.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649729","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 : 2025-03-17DOI: 10.1038/s43018-025-00933-2
Jinming Wang, Penghui Xu, Zhongzhong Ji, Chaping Cheng, Yiyun Liu, Genyu Du, Shilei Zhang, Juju Miao, Deng Wang, Ruoyang Chen, Dawei Li, Kai Zhang, Huifang Zhao, Yujiao Sun, Xinyu Chen, Na Jing, Kaiyuan Liu, Yuman He, Xialian Xi, Yingchao Zhang, Nan Wang, Longmei Xu, Jufang Yao, Xiaomei Gao, Jianhua Zhou, Songqing Fan, Xiaorui Wang, Shuxian Dong, Fangli Chen, Jian Hou, Ming Zhang, Wei-Qiang Gao, Lijing Shen, Pengcheng Zhang, Helen He Zhu
{"title":"A Gremlin 1-expressing splenic niche cell population restrains chronic myeloid leukemia by antagonizing the BMP pathway.","authors":"Jinming Wang, Penghui Xu, Zhongzhong Ji, Chaping Cheng, Yiyun Liu, Genyu Du, Shilei Zhang, Juju Miao, Deng Wang, Ruoyang Chen, Dawei Li, Kai Zhang, Huifang Zhao, Yujiao Sun, Xinyu Chen, Na Jing, Kaiyuan Liu, Yuman He, Xialian Xi, Yingchao Zhang, Nan Wang, Longmei Xu, Jufang Yao, Xiaomei Gao, Jianhua Zhou, Songqing Fan, Xiaorui Wang, Shuxian Dong, Fangli Chen, Jian Hou, Ming Zhang, Wei-Qiang Gao, Lijing Shen, Pengcheng Zhang, Helen He Zhu","doi":"10.1038/s43018-025-00933-2","DOIUrl":"https://doi.org/10.1038/s43018-025-00933-2","url":null,"abstract":"<p><p>The spleen plays a critical role in the pathogenesis of leukemia. However, our understanding of the splenic niche is very limited. Herein, we report that induced expression of the secreted protein Gremlin 1 in a mouse model restrains chronic myeloid leukemia (CML) progression and synergizes with tyrosine kinase inhibitor treatment, whereas blockade of Gremlin 1 promotes CML development. Intriguingly, the effect of Gremlin 1 is most evident in the spleen but not in the bone marrow. Gremlin 1 induces apoptosis of leukemic stem cells via antagonizing the BMP pathway. Single-cell RNA sequencing and experimental validation together show that Gremlin 1 marks a unique stromal cell population in the spleens of both mice and humans. Genetic ablation of Gremlin 1<sup>+</sup> cells leads to accelerated CML progression. Collectively, Gremlin 1 and Gremlin 1<sup>+</sup> cells are key defensive niche components in the spleen that limit CML progression, revealing an unprecedented mechanism for the body to fight off leukemia.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649639","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 both death and paracaspase domains of MALT1 with antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors.","authors":"Yuwei Tao, Chen Tian, Shaolong Qi, Ziqi Jia, Zheng Xu, Jingjing Meng, Guoyuan Xu, Haitian Hu, Xuxiang Wang, Tengjiang Zhang, Huiwen You, Xun Lan, Xin Lin, Guocan Yu, Haitao Zhou, Jiaqi Liu, Hanqiu Zheng","doi":"10.1038/s43018-025-00930-5","DOIUrl":"https://doi.org/10.1038/s43018-025-00930-5","url":null,"abstract":"<p><p>Targeting MALT1's paracaspase activity has been explored for B cell lymphoma and solid tumors. While the role of MALT1 in promoting cancer cell proliferation has been investigated, its involvement in immune evasion is unclear. Here we report that MALT1 promotes immune evasion through its paracaspase and death domain. In a paracaspase-dependent manner, MALT1 protects CD274 mRNA from degradation by its cleavage of ROQUIN1 and ROQUIN2. In a death-domain-dependent manner, MALT1 promotes the proliferation and polarization of tumor-associated macrophages to generate an immunosuppressive tumor microenvironment. Targeting MALT1 with antisense oligonucleotides inhibits PD-L1 expression in patient-derived tumor cells and suppresses the proliferation and M2-like polarization of tumor-associated macrophages isolated from patients with cancer. In preclinical models of solid tumors in female mice, treatment with MALT1 antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors. Together, our study demonstrates that targeting MALT1 is a potential strategy to overcome immune-checkpoint inhibitor resistance.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616285","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 : 2025-03-12DOI: 10.1038/s43018-025-00938-x
Vincenzo Giacco
{"title":"Long-term results with nivolumab and ipilimumab in melanoma.","authors":"Vincenzo Giacco","doi":"10.1038/s43018-025-00938-x","DOIUrl":"https://doi.org/10.1038/s43018-025-00938-x","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":23.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616283","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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