Oncogene最新文献

{"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":"https://doi.org/10.1038/s41388-026-03971-x","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1038/s41388-026-03970-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Matti Nykter, Lauri A Aaltonen, Alfonso Urbanucci, Anna Lepistö, Ari Ristimäki, Toni T Seppälä","doi":"10.1038/s41388-026-03957-9","DOIUrl":"https://doi.org/10.1038/s41388-026-03957-9","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1038/s41388-026-03961-z","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"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":"<p><p>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.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1038/s41388-026-03936-0","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"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}

{"title":"The Inv(16) Oncogene CBFB::MYH11 is Required for the Survival of Leukemia Cells in the Blood and Spleen, but not the Bone Marrow.","authors":"Sipra Panda, Yiqian Wang, Venkatasai Rahul Dogiparthi, Michelle Becker, Arjun Dhir, Calvin Lam, Cecilia Rivas, Lemlem Alemu, Lisa Garrett, Peng Xiao, Samantha A Swenson, Kyle J Hewitt, R Katherine Hyde","doi":"10.1038/s41388-026-03956-w","DOIUrl":"10.1038/s41388-026-03956-w","url":null,"abstract":"<p><p>Inversion of chromosome 16 [inv(16)] generates the fusion gene CBFB::MYH11 (CM) and is one of the most common chromosomal rearrangements in Acute Myeloid Leukemia (AML). Expression of CM is required for leukemia initiation. Patients with inv(16) at diagnosis invariably have the rearrangement at relapse, leading to the assumption that CM is also required after leukemic transformation. However, a role for CM in leukemia maintenance has yet to be shown experimentally. To address this, we used an inducible CM knockdown (KD) mouse model and found that decreased CM eliminated leukemia cells from the peripheral blood and spleen, but not the bone marrow, despite all populations exhibiting significantly decreased CM mRNA and protein. The surviving CM KD cells in the bone marrow showed decreased apoptosis and proliferation, and increased expression of autophagy related genes. Surprisingly, with prolonged KD of CM, ~40% of mice re-established disease despite maintaining decreased CM. Our work indicates that CM is required for leukemia survival in the spleen and peripheral blood, but in the bone marrow CM KD leukemia cells can survive and re-establish disease independent of the fusion protein. These findings imply that targeting CM alone has potential to reduce leukemic burden but not cure the disease.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148796293","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":"Imbalanced p53-RB signaling triggers cGAS-STING-mediated immune activation in early oral cancer development.","authors":"Zichao Lu, Yasuhiro Mouri, Wenhua Shao, Akihiro Yasue, Chunhua Wang, Hiroko Hagita, Kiyotake Yamamoto, Naoko Matsumoto, Minoru Matsumoto, Takeshi Oya, Yasusei Kudo","doi":"10.1038/s41388-026-03962-y","DOIUrl":"https://doi.org/10.1038/s41388-026-03962-y","url":null,"abstract":"<p><p>Combined alterations of TP53 and CDKN2A are frequently observed in head and neck squamous cell carcinoma (HNSCC); however, their cooperative roles in oral carcinogenesis remain unclear. To investigate their interaction under carcinogenic stress, we generated Cdkn2a knock-in (KI) mice harboring a human-relevant R80X truncating mutation, along with Trp53 loss-of-function (LOF) mutants and exposed them to 4-nitroquinoline-1-oxide (4NQO). Partial loss of Cdkn2a combined with Trp53 heterozygosity was associated with increased STING-related inflammatory signaling and enhanced T-cell/NK-cell-associated immune infiltration, coinciding with delayed malignant progression. Enhanced production of proinflammatory cytokines and chemokines further indicated selective activation of the cGAS-STING-NF-κB axis. Analysis of the TCGA-HNSC cohort showed that combined TP53/CDKN2A alterations significantly separated overall survival and were associated with distinct survival patterns. These findings reveal a previously unrecognized mechanism by which imbalanced p53-RB signaling triggers tumor immunity during the early stages of oral carcinogenesis.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762659","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":"Inhibition of PINK1/Parkin-mediated mitophagy enhances the susceptibility of breast cancer to cuproptosis.","authors":"Chaoyi Tang, Ka Su, Zexu Zhan, Rongzhi Huang, Ming Luo, Jiehua Li","doi":"10.1038/s41388-026-03945-z","DOIUrl":"https://doi.org/10.1038/s41388-026-03945-z","url":null,"abstract":"<p><p>Cuproptosis is a novel form of programmed cell death characterized by the accumulation of copper ions in the mitochondria, the formation of DLAT oligomers, and the depletion of Fe-S cluster proteins. However, the alterations in mitochondrial morphology and function during cuproptosis and the potential role of mitophagy in cuproptosis remain insufficiently elucidated. In this study, we induced cuproptosis of breast cancer cells using Elesclomol (ES) and assessed changes in mitochondrial reactive oxygen species, mitochondrial membrane potential, and oxygen consumption rate. Stable cell lines with overexpression or knockdown of PINK1/Parkin genes were constructed to elucidate the impact of mitophagy on cuproptosis. Subcutaneous mouse xenograft models were employed to identify drugs that may synergize with ES and enhance antitumor effects. Our results demonstrated that ES induced cuproptosis of breast cancer cells, which was associated with the activation of PINK1/Parkin-mediated mitophagy. Both gene knockdown and pharmacological inhibition of mitophagy enhanced the sensitivity of breast cancer cells to cuproptosis in vitro and in vivo. The combination of dichloroacetate (DCA) and ES exhibited a synergistic antitumor effect without significant tissue damage on the brain, heart, liver, and kidneys in subcutaneous mouse xenograft models. Collectively, our findings reveal that inhibiting PINK1/Parkin-mediated mitophagy enhances the sensitivity of breast cancer to cuproptosis, offering a novel combined treatment strategy for breast cancer.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761913","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 SELP/PSGL1 axis reprograms M2 macrophages and enhances anti-PD-1 efficacy in gastric cancer.","authors":"Yue Wu, Xiaobo Peng, Tong Yin, Xiaoxiao Wu, Jingyu Liu, Yulin Xing, Xian Liu, Shuhui Tang, Xiaoxiao Li, Xianbao Zhan","doi":"10.1038/s41388-026-03942-2","DOIUrl":"10.1038/s41388-026-03942-2","url":null,"abstract":"<p><p>Immune evasion and an immunosuppressive tumor microenvironment contribute to the poor prognosis of gastric cancer (GC), but the mechanisms governing tumor-associated macrophage (TAM) polarization remain unclear. Here we identify P-selectin (SELP) as a key driver of GC progression and immune suppression. SELP was markedly upregulated in GC and correlated with advanced stage, increased M2 macrophage infiltration, and poor survival. Mechanistically, SELP engaged PSGL1 on TAMs to activate PI3K/AKT/mTOR signaling, which enhanced glycolysis and lactate production. Lactate in turn induced MYB, thereby promoting SELP transcription and establishing a feed-forward circuit that sustained M2-like polarization. Therapeutically, genetic or pharmacological targeting of SELP reprogrammed TAMs towards a pro-inflammatory state, increased intratumoural CD8⁺ T-cell infiltration, and inhibited tumor growth. Moreover, SELP inhibition with KF38789 potentiated the antitumour efficacy of PD-1 blockade in syngeneic GC models. Together, these findings define a SELP/PSGL1-PI3K/AKT/mTOR-lactate-MYB signaling axis that promotes macrophage-mediated immune evasion in GC and highlight SELP as a potential therapeutic target for improving immunotherapy response.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148721807","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}