Oncogene最新文献

{"title":"POC1A promotes the proliferation, metastasis and stemness of bladder cancer by stabilizing BMI1 via USP7","authors":"Houyi Wei, Renran Bai, Jianmin Liu, Lei Lyu, Jingdong Yuan, Wan Xiang, Kaiyu Qian, Fangjin Chen, Lingao Ju, Yi Zhang, Yu Xiao, Gang Wang","doi":"10.1038/s41388-026-03973-9","DOIUrl":"10.1038/s41388-026-03973-9","url":null,"abstract":"Advanced bladder cancer (BLCA), a malignancy with high recurrence, carries a dismal prognosis, demanding the identification of novel therapeutic targets. In this study, we aim to investigate a critical molecular mechanism driving BLCA progression. By integrating published sequencing datasets, we identified that POC1A is overexpressed in BLCA tissues, a factor positively correlated with advanced stage, high grade, disease progression, and inversely correlated with overall survival. In vitro and in vivo analyses indicate that POC1A knockdown inhibits BLCA cell proliferation, metastasis, and stemness. Mechanistically, POC1A functions as a scaffold protein, forming a complex with USP7 and BMI1. This enhances the USP7-BMI1 interaction, reduces BMI1 ubiquitination in a USP7-dependent manner, and consequently stabilizes the BMI1 protein. The functional significance of this pathway was confirmed as overexpression of either BMI1 or USP7 rescued the inhibitory phenotypes induced by POC1A knockdown. Furthermore, pharmacological targeting of BMI1 with Unesbulin suppressed BLCA growth in cell-line and patient-derived xenograft models, supporting the therapeutic tractability of the POC1A-BMI1 axis. Taken together, these findings reveal that POC1A facilitates the USP7-mediated deubiquitination and stabilization of BMI1, establishing the POC1A-USP7-BMI1 complex as a compelling therapeutic target in BLCA.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 42","pages":"4498-4511"},"PeriodicalIF":9.1,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865737","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":"DHCR24+ tumor epithelial cells drive cisplatin resistance in bladder cancer by enhancing cholesterol metabolism to activate lipid raft-associated MAPK signaling","authors":"Yuanqiao Zhao, Zhuo Xing, Mengmeng Wang, Liangmin Fu, Ruilin Liu, Zexian Ding, Yuan Li, Yinhuai Wang, Bin Yan, Xueqiang Zhu","doi":"10.1038/s41388-026-03967-7","DOIUrl":"10.1038/s41388-026-03967-7","url":null,"abstract":"Cisplatin-based combination therapy remains the primary treatment modality for patients with advanced bladder cancer (BCa); however, the emergence of drug resistance severely restricts clinical benefits. The molecular mechanisms underlying chemoresistance remain incompletely understood. By integrating single-cell transcriptomics with in vitro and in vivo experiments, we revealed that cholesterol metabolism was significantly hyperactivated in cisplatin-resistant BCa tissues. Further subpopulation re-clustering identified a specific chemoresistant epithelial cell subset (C3) characterized by robust cholesterol metabolism, in which the cholesterol metabolic enzyme DHCR24 was significantly upregulated and played a pivotal role in mediating cisplatin resistance in BCa. Mechanistically, the elevated expression of TFDP1 in cisplatin-resistant BCa epithelial cells upregulated DHCR24 via the formation of the TFDP1-E2F1 transcriptional complex, thereby promoting cholesterol biosynthesis. The enriched intracellular cholesterol facilitated the formation of cell membrane lipid rafts and enhanced the phosphorylation of Src, which in turn hyperactivated the downstream MAPK signaling pathway, ultimately conferring cisplatin resistance. Furthermore, the accumulated cholesterol enhanced PD-L1 protein stability, thereby impairing the efficacy of immunotherapy in BCa. Taken together, our study characterizes a specific DHCR24+ tumor epithelial subpopulation that orchestrates cisplatin resistance via the “cholesterol-lipid raft-MAPK” axis. These findings establish a clear mechanistic link between cholesterol metabolism and cisplatin sensitivity.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 41","pages":"4454-4470"},"PeriodicalIF":9.1,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857551","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":"Correction: E-cadherin is a biomarker for ferroptosis sensitivity in diffuse gastric cancer","authors":"Alexander M. Minikes, Yu Song, Yan Feng, Changhwan Yoon, Sam S. Yoon, Xuejun Jiang","doi":"10.1038/s41388-026-03963-x","DOIUrl":"10.1038/s41388-026-03963-x","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 37","pages":"3997-3999"},"PeriodicalIF":9.1,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03963-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840877","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":"SEC14L2 contributes to tumor progression by enhancing USP5-driven RBM3 deubiquitination in pancreatic ductal adenocarcinoma","authors":"Zengyu Feng, Kai Qin, Haocheng Yu, Chuanshuai Lin, Yuheng Tu, Jianyao Lou, Kexian Li, Juyong Liang, Hongxia Xu, Chenghong Peng","doi":"10.1038/s41388-026-03968-6","DOIUrl":"10.1038/s41388-026-03968-6","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) persists as a highly lethal malignancy with a dire prognosis and scarce therapeutic advancements, highlighting an urgent demand for innovative prognostic markers and molecular targets. Herein, we identify Section 14-like lipid binding 2 (SEC14L2) as a pivotal oncogene in PDAC pathogenesis. Elevated SEC14L2 expression is established as a potent and consistent prognostic indicator, strongly associated with adverse clinical outcomes across multiple independent patient cohorts. Functional analyses confirm that SEC14L2 drives malignant progression by enhancing proliferation and inhibiting apoptosis in PDAC cells. Mechanistically, we elucidate that SEC14L2 orchestrates the recruitment of ubiquitin-specific-processing protease 5 (USP5) to RNA-binding motif protein 3 (RBM3). This interaction facilitates USP5-mediated deubiquitination of RBM3 at lysine 84, specifically cleaving K48-linked polyubiquitin chains, which consequently stabilizes the RBM3 protein. The accumulated RBM3 then augments the mRNA stability of doublecortin-like kinase 1 (DCLK1), a recognized mediator of tumorigenesis. Furthermore, we uncover that the transcription factor SP1 acts as a key upstream regulator, directly governing the transcriptional activation of SEC14L2 and fostering its frequent upregulation in PDAC. Our findings delineate a novel SP1/SEC14L2/USP5/RBM3/DCLK1 signaling axis that critically propels PDAC progression, thereby nominating SEC14L2 as a compelling therapeutic target for this devastating disease.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 41","pages":"4406-4419"},"PeriodicalIF":9.1,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148831086","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":"Decitabine suppresses triple-negative breast cancer by disrupting DNMT1 liquid-liquid phase separation and synergizes with G9a inhibition","authors":"Meilin Hu, Haojie Peng, Guochang Qiu, Sen Liu, Qianying Li, Taizhen Liang, Jintao Lai, Fenmei Liang, Yiqiang Zhu, Xiaoqing Liu, Lixiang Xie, Yaoming Liu, Tao Chen, Bin Zhang, Haiyue Rao, Shiqi Xiao, Peiwen Li, Xiancai Ma, Xinxin Chen","doi":"10.1038/s41388-026-03971-x","DOIUrl":"10.1038/s41388-026-03971-x","url":null,"abstract":"Triple-negative breast cancer (TNBC) remains a substantial clinical challenge due to the lack of well-defined therapeutic targets. Previous studies have demonstrated that epigenetic modifiers play crucial roles in the progression of various cancers. In this study, we identify DNA methyltransferase 1 (DNMT1) as a critical epigenetic driver of TNBC proliferation and metastasis. Our findings show that DNMT1 is highly expressed in TNBC and forms liquid-liquid phase separation (LLPS) condensates. Knockout of DNMT1 sensitizes TNBC cells to apoptosis and lipid peroxidation, downregulates oncogenic pathways, and upregulates apoptosis-related genes. The DNMT1 inhibitor decitabine (DAC) disrupts DNMT1 condensates, consequently inducing apoptosis and lipid peroxidation. Mechanistically, DAC directly binds to the disordered domain of DNMT1, thereby dissolving LLPS condensates and impairing epigenetic silencing. Remarkably, DAC synergizes with histone methyltransferase G9a inhibitor BIX-01294 (BIX) to suppress TNBC proliferation, migration, and invasion. Combined treatment with DAC and BIX significantly inhibits lung metastasis in murine and human TNBC mouse models, reducing proliferative cancer cells and metastatic burden. This study reveals DNMT1 LLPS as a druggable vulnerability in TNBC and establishes LLPS disruption as a promising therapeutic strategy, providing a rationale for combining epigenetic inhibitors to treat TNBC and other cancers with high DNMT1 expression.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 41","pages":"4420-4441"},"PeriodicalIF":9.1,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03971-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148831136","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":"Genome-wide CRISPR screens identify an RXR–MYLIP–LDLR axis regulating BH3 mimetic sensitivity in peripheral T-cell lymphomas","authors":"Keito Yokoyama, Masahiro Chiba, Norio Takei, Keito Suto, Takashi Ishio, Hideki Goto, Tomoyuki Endo, Marshall E. Kadin, Michiyuki Maeda, Masashi Watanabe, Shigetsugu Hatakeyama, Takanori Teshima, Yibin Yang, Masao Nakagawa","doi":"10.1038/s41388-026-03970-y","DOIUrl":"10.1038/s41388-026-03970-y","url":null,"abstract":"BH3 mimetics are a promising class of drugs in hematologic malignancies, but their efficacy in peripheral T-cell lymphoma (PTCL) remains poorly understood. To identify genetic determinants of BH3 mimetic response, we performed a genome-wide CRISPR-Cas9 knockout screen in PTCL cell lines and identified MYLIP, an E3 ubiquitin ligase targeting the LDL receptor (LDLR), as a novel sensitizer to navitoclax. MYLIP deletion enhanced the cytotoxicity of navitoclax, venetoclax, and the BCL-XL–selective degrader DT2216 across multiple PTCL models. Mechanistically, MYLIP loss increased LDLR expression, promoted cholesterol uptake, and elevated apoptotic priming. Recombinant PCSK9, which facilitates LDLR degradation, reversed MYLIP knockout–induced sensitization, establishing a functional role for LDLR in BH3 mimetic response. We also identified the nuclear receptor RXRB as an upstream regulator of MYLIP; dual RXRA/RXRB depletion more effectively suppressed MYLIP, upregulated LDLR, and potentiated navitoclax cytotoxicity. In vivo, MYLIP-deficient xenografts showed enhanced tumor suppression with navitoclax treatment. Transcriptomic analyses of primary PTCL samples revealed reduced MYLIP expression in ALK-positive anaplastic large cell lymphoma and genetically defined subsets of nodal T follicular helper cell lymphomas. These findings uncover an RXR–MYLIP–LDLR axis that links cholesterol metabolism to apoptotic susceptibility, offering mechanistic insight into BH3 mimetic sensitivity in PTCL.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 41","pages":"4393-4405"},"PeriodicalIF":9.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03970-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148819267","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":"Epithelial interferon-stimulated gene programs modulate chemotherapy sensitivity in colorectal cancer via EPSTI1","authors":"Erdogan Pekcan Erkan, Emmi Hämäläinen, Julia Kolikova, Tiia Nikupaavola, Karishma Sajnani, Kornelia Kuc, Kalle Ojala, Meiju Kukkonen, Ismaïl Hermelo, Antti Kurttila, Selja Koskensalo, Timo Tarvainen, Alli Leppä, Ilona Keränen, Carola Haapamäki, Essi Karjalainen, Monika Carpelan-Holmström, Laura Renkonen-Sinisalo, Laura Koskenvuo, Pauli Puolakkainen, Jukka-Pekka Mecklin, Juha P. Väyrynen, Elina Virolainen, iCAN, Matti Nykter, Lauri A. Aaltonen, Alfonso Urbanucci, Anna Lepistö, Ari Ristimäki, Toni T. Seppälä","doi":"10.1038/s41388-026-03957-9","DOIUrl":"10.1038/s41388-026-03957-9","url":null,"abstract":"Although chemotherapy in colorectal cancer (CRC) primarily targets epithelial tumor cells, the epithelial cell-intrinsic mechanisms underlying heterogeneous treatment responses remain poorly understood. We integrated the genomic, transcriptomic, and in vitro drug response profiles of CRC patient-derived tumor organoids (PDTOs) with functional assays to identify epithelial cell-intrinsic determinants of chemotherapy response. An epithelial interferon-stimulated gene (ISG) program, reflecting JAK-STAT pathway activity, was associated with reduced chemosensitivity in PDTOs. Single-cell RNA sequencing data of CRC tumors before and after neoadjuvant chemotherapy showed persistent epithelial ISG expression, with EPSTI1 notably enriched in tumors with incomplete pathological responses. Functional studies demonstrated that EPSTI1 knockdown reduced CRC cell viability and enhanced chemosensitivity. Pharmacologic JAK-STAT inhibition with ruxolitinib suppressed ISG expression and attenuated chemotherapy-induced ISG upregulation. These findings highlight the utility of PDTOs for studying tumor-intrinsic mechanisms of treatment response and identify EPSTI1 as an epithelial modulator of chemosensitivity.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 41","pages":"4377-4392"},"PeriodicalIF":9.1,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03957-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148796333","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":"Cholangiocarcinoma:Unveiling the cold tumor microenvironment and strategies for immune rejuvenation","authors":"Wenqi Xu, Shuhan Liu, Longlong Sun, Yao Bi, Zhenhua Lin, Tong Wang, Xiangshan Ren, Renbo An","doi":"10.1038/s41388-026-03961-z","DOIUrl":"10.1038/s41388-026-03961-z","url":null,"abstract":"Cholangiocarcinoma (CCA) remains a therapeutic challenge due to its “immune cold” phenotype, defined by a desmoplastic fortress and profound T cell exclusion. This review characterizes the multi layered immune escape mechanisms, ranging from defective antigen presentation to the recruitment of suppressive myeloid cells and fibroblasts. We detail how physical barriers and the gut-liver axis conspire to maintain immune invisibility. Moving beyond mechanism, we critically evaluate emerging strategies designed to breach these defenses and reprogram the tumor microenvironment, including stromal targeting, mRNA vaccines, and combinatorial immunotherapies. We conclude by delineating the paradigm shift toward precision immuno oncology, highlighting that resolving spatiotemporal heterogeneity through multi-omics integration is essential for transforming CCA into an immune responsive state. Additionally, the synergy between AI and intelligent medicine provides a novel roadmap for advancing CCA clinical therapeutics.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 39","pages":"4101-4116"},"PeriodicalIF":9.1,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148796304","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":"PTEN-AKT2 regulates mixed lineage liver cancer development and sensitizes cancer cells to TGFβ treatment","authors":"Qi Tang, Ielyzaveta Slarve, Jingyu Chen, Ni Zeng, Yiwei Gu, Lina He, Shunan Hu, Diala Alhousari, Zifei Xu, Brittney Hua, Guo Zhang, Phillip Nguyen, Mario Alba, Ajay Bharadwaj, Jihyeon Lee, Simion Kreimer, Jian Xu, Baoan Ji, Shelly C. Lu, Jennifer Van Eyk, Shefali Chopra, Gary Kanel, Liyun Yuan, Bangyan L. Stiles","doi":"10.1038/s41388-026-03960-0","DOIUrl":"10.1038/s41388-026-03960-0","url":null,"abstract":"Primary liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), arise from the neoplastic transformation of hepatocytes and cholangiocytes, respectively. Loss or downregulation of PTEN, a tumor suppressor negatively regulating the PI3K/AKT pathway, is frequently observed in CCA and HCC. Notably, PTEN mutations are observed at nearly twice the frequency in combined CCA-HCC tumors than either HCC or CCA alone. Using lineage-specific liver-targeted PTEN-deficient mouse models, we demonstrate that PTEN loss drives cellular dedifferentiation and tumorigenesis, a process that is critically dependent on AKT2. Mechanistically, PTEN deficiency induces activation of NOTCH and upregulation of transcriptional factor SOX9, which plays a central role in tumor cell transformation. In parallel, PTEN loss increases SMAD4 expression and sensitizes the tumor cells to TGFβ signaling, with TGFβ treatment repressing SOX9 expression in tumor cells lacking PTEN. Together, our study defined a critical role for PTEN-AKT2 signaling in maintaining liver epithelial lineage fidelity and revealed how its disruption promotes the conversion of mature hepatocytes or cholangiocytes into liver cancer stem-like cells (LCSCs). Furthermore, we identify a PTEN-dependent crosstalk between NOTCH and TGFβ pathways that governs liver tumor development. Together, this work provides mechanistic insight into lineage plasticity in liver cancer with implications for pathway-directed therapy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 41","pages":"4362-4376"},"PeriodicalIF":9.1,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03960-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148796286","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":"Tumor-derived PTX3 drives an immunosuppressive myeloid landscape and inhibits CD8 T cell-mediated anti-tumor immunity via PI3K-dependent signaling","authors":"Mohamed Y. Zaky, Monika Vashisht, Mohammad A. I. Al-Hatamleh, Karen Siddoway, Jennifer Yan, Anthony Bragoli, Jessy John, Huaibin Ge, Zhangguo Chen, Jing H. Wang","doi":"10.1038/s41388-026-03936-0","DOIUrl":"10.1038/s41388-026-03936-0","url":null,"abstract":"Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a pillar of modern oncology. However, clinical response rates in head and neck squamous cell carcinoma (HNSCC) remain modest, underscoring the need to identify novel therapeutic targets. Here, we investigated the role of Pentraxin 3 (PTX3) in orchestrating an immunosuppressive tumor microenvironment (TME) in HNSCC. Analysis of the TCGA dataset revealed that elevated PTX3 expression correlates with poor prognosis in HNSCC patients. Moreover, PTX3 is markedly upregulated in aggressive, ICI-resistant TAb2 tumors harboring an activated PIK3CA allele and TP53 deficiency. Using a CRISPR/Cas9 approach to delete PTX3 in TAb2 cells (PTX3-KO), we found that PTX3-KO tumors grew significantly slower than wild-type tumors in vivo. This reduced tumor growth was partially dependent on CD8+ T cells and occurred independently of tumor-intrinsic effects on cell proliferation. Genetic deletion of PTX3 profoundly reprogrammed the TME, increasing CD8+ tumor-infiltrating lymphocytes (TILs) and shifting the myeloid landscape by reducing immunosuppressive M2-like tumor-associated macrophages (TAMs) while promoting pro-inflammatory M1-like TAMs. Mechanistically, PTX3 drives M2-TAM polarization by activating downstream PI3K-γ/δ-dependent signaling, with evidence implicating the CD44 receptor. Crucially, anti-CD44 treatment or pharmacological blockade of PI3K-γ or PI3K-δ phenocopied the effects of PTX3 loss, substantially reducing M2-like TAMs and elevating M1-like TAMs. Collectively, our findings establish the innate immune molecule PTX3 as a critical regulator of myeloid-driven immune suppression in HNSCC. While PTX3 deficiency alone did not sensitize these models to PD-L1 blockade, therapeutic targeting of the PTX3-CD44-PI3K axis represents a promising strategy for remodeling the immunosuppressive TME. Head and neck cancer is a major global health challenge. Many patients fail to respond to current treatments because components within tumor microenvironments suppress immune responses. This study aimed to understand how a protein made by cancer cells, called PTX3, helps tumors hide from the immune system. To investigate this, researchers used gene-editing technology to remove PTX3 from cancer cells in laboratory models and monitored the immune response. They discovered that removing PTX3 significantly slowed tumor growth. Without this protein, harmful, immune-suppressing cells were reduced, while protective, cancer-fighting cells were increased to attack tumors. These findings show that PTX3 helps tumors block immune defenses. Disrupting this protein or its downstream signals represents a promising approach to develop more effective therapies that could help patients successfully fight head and neck cancers.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 40","pages":"4330-4344"},"PeriodicalIF":9.1,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148796274","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}