Molecular Cancer最新文献

{"title":"Dual role of interferon-gamma in the response of melanoma patients to immunotherapy with immune checkpoint inhibitors","authors":"Piotr Wawrzyniak, Mariusz L. Hartman","doi":"10.1186/s12943-025-02294-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02294-x","url":null,"abstract":"Interferon-gamma (IFN-γ) is a cytokine produced mainly by immune cells and can affect cancer cells by modulating the activity of multiple signaling pathways, including the canonical Janus-activated kinase/signal transducer and activator of transcription (JAK/STAT) cascade. In melanoma, IFN-γ can exert both anticancer effects associated with cell-cycle arrest and cell death induction and protumorigenic activity related to immune evasion leading to melanoma progression. Notably, IFN-γ plays a crucial role in the response of melanoma patients to immunotherapy with immune checkpoint inhibitors (ICIs), which are currently used in the clinic. As these agents target programmed death-1 (PD-1) and its ligand (PD-L1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and lymphocyte-activation gene 3 (LAG-3), they are designed to restore the antimelanoma immune response. In this respect, IFN-γ produced by cells in the tumor microenvironment in response to ICIs has a beneficial influence on both immune and melanoma cells by increasing antigen presentation, recruiting additional T-cells to the tumor site, and inducing direct antiproliferative effects and apoptosis in melanoma cells. Therefore, IFN-γ itself and IFN-γ-related gene signatures during the response to ICIs can constitute biomarkers or predictors of the clinical outcome of melanoma patients treated with ICIs. However, owing to its multifaceted roles, IFN-γ can also contribute to developing mechanisms associated with the acquisition of resistance to ICIs. These mechanisms can be associated with either decreased IFN-γ levels in the tumor microenvironment or diminished responsiveness to IFN-γ due to changes in the melanoma phenotypes associated with affected activity of other signaling pathways or genetic alterations e.g., in JAK, which restricts the ability of melanoma cells to respond to IFN-γ. In this respect, the influence of IFN-γ on melanoma-specific regulators of the dynamic plasticity of the cell phenotype, including microphthalmia-associated transcription factor (MITF) and nerve growth factor receptor (NGFR)/CD271 can affect the clinical efficacy of ICIs. This review comprehensively discusses the role of IFN-γ in the response of melanoma patients to ICIs with respect to its positive influence and role in IFN-γ-related mechanisms of resistance to ICIs as well as the potential use of predictive markers on the basis of IFN-γ levels and signatures of IFN-γ-dependent genes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"34 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661313","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":"DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer","authors":"Benjamin B. Morris, Simon Heeke, Yuanxin Xi, Lixia Diao, Qi Wang, Pedro Rocha, Edurne Arriola, Myung Chang Lee, Darren R. Tyson, Kyle Concannon, Kavya Ramkumar, C. Allison Stewart, Robert J. Cardnell, Runsheng Wang, Vito Quaranta, Jing Wang, John V. Heymach, Barzin Y. Nabet, David S. Shames, Carl M. Gay, Lauren A. Byers","doi":"10.1186/s12943-025-02291-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02291-0","url":null,"abstract":"A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes. To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is associated with SCLC biology, chemotherapy response, and tumor evolution following therapy. Using multi-omic profiling, we demonstrate that SCLC tumors cluster into three DDR phenotypes with unique molecular features. Hallmarks of these DDR clusters include differential expression of DNA repair genes, increased replication stress, and heightened G2/M cell cycle arrest. SCLCs with elevated DDR phenotypes exhibit increased neuroendocrine features and decreased “inflamed” biomarkers, both within and across SCLC subtypes. Clinical analyses demonstrated treatment naive DDR status was associated with different responses to frontline chemotherapy. Using longitudinal liquid biopsies, we found that DDR Intermediate and High tumors exhibited subtype switching and coincident emergence of heterogenous phenotypes following frontline treatment. We establish that SCLC can be classified into one of three distinct, clinically relevant DDR clusters. Our data demonstrates that DDR status plays a key role in shaping SCLC phenotypes and may be associated with different chemotherapy responses and patterns of tumor evolution. Future work targeting DDR specific phenotypes will be instrumental in improving patient outcomes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"11 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661310","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":"Extracellular vesicles in cancer´s communication: messages we can read and how to answer","authors":"Alena Semeradtova, Michaela Liegertova, Regina Herma, Magdalena Capkova, Chiara Brignole, Genny Del Zotto","doi":"10.1186/s12943-025-02282-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02282-1","url":null,"abstract":"Extracellular vesicles (EVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME), profoundly influencing cancer progression. These nano-sized vesicles, released by both tumor and stromal cells, carry a diverse cargo of proteins, nucleic acids, and lipids, reflecting the dynamic cellular landscape and mediating intricate interactions between cells. This review provides a comprehensive overview of the biogenesis, composition, and functional roles of EVs in cancer, highlighting their significance in both basic research and clinical applications. We discuss how cancer cells manipulate EV biogenesis pathways to produce vesicles enriched with pro-tumorigenic molecules, explore the specific contributions of EVs to key hallmarks of cancer, such as angiogenesis, metastasis, and immune evasion, emphasizing their role in shaping TME and driving therapeutic resistance. Concurrently, we submit recent knowledge on how the cargo of EVs can serve as a valuable source of biomarkers for minimally invasive liquid biopsies, and its therapeutic potential, particularly as targeted drug delivery vehicles and immunomodulatory agents, showcasing their promise for enhancing the efficacy and safety of cancer treatments. By deciphering the intricate messages carried by EVs, we can gain a deeper understanding of cancer biology and develop more effective strategies for early detection, targeted therapy, and immunotherapy, paving the way for a new era of personalized and precise cancer medicine with the potential to significantly improve patient outcomes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"90 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653394","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":"Autophagy in tumor immune escape and immunotherapy","authors":"Huan Wang, Peng Sun, Xijing Yuan, Zhiyong Xu, Xinyuan Jiang, Mingshu Xiao, Xin Yao, Yueli Shi","doi":"10.1186/s12943-025-02277-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02277-y","url":null,"abstract":"The immunotherapy targeting tumor immune escape mechanisms has become a critical strategy in anticancer treatment; however, the challenge of immune resistance remains significant. Autophagy, a cellular response to various stressors, involves the degradation of damaged proteins and organelles via lysosomal pathways, maintaining cellular homeostasis. This process not only supports tumor cell survival but also profoundly impacts the efficacy of cancer immunotherapies. The modulation of autophagy in tumor cells or immune cells exerts dual effects on tumor immune escape and immunotherapy. However, the mechanistic details of how autophagy influences the immune system and therapy remain inadequately understood. Given this complexity, a deeper understanding of the role of autophagy in the tumor-immune landscape could reveal novel therapeutic avenues. By manipulating autophagy appropriately, it may be possible to overcome immune resistance and enhance the effectiveness of immunotherapeutic strategies. This article summarizes the role of autophagy in tumor immunity, its relationship with immunotherapy, and the potential therapeutic benefits of targeting autophagy to strengthen antitumor immune responses and optimize the outcomes of immunotherapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"33 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653395","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":"Retraction Note: Loss of vinculin and membrane-bound β-catenin promotes metastasis and predicts poor prognosis in colorectal cancer","authors":"Ting Li, Hanqing Guo, Ying Song, Xiaodi Zhao, Yongquan Shi, Yuanyuan Lu, Sijun Hu, Yongzhan Nie, Daiming Fan, Kaichun Wu","doi":"10.1186/s12943-025-02304-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02304-y","url":null,"abstract":"<p><b>Retraction note: </b><b><i>Mol Cancer</i></b><b>13, 263 (2014)</b></p><p><b>https://doi.org/10.1186/1476-4598-13-263</b></p><p>The Editor-in-Chief and the Publisher have retracted this article. Ten instances of apparent image duplication, some with rotation and contrast changes, were found within and across Figs. 2 and 3, and 6. An investigation by the publisher confirmed several image integrity issues, including but not limited to the reuse of control and figures appearing to overlap after apparent rotation or resizing. Therefore, the Editor-in-Chief no longer has confidence in the results and conclusions of this article.</p><p>Authors Sijun Hu and Yuanyuan Lu could not be contacted by the Publisher. The remaining Authors have not responded to correspondence regarding this retraction.</p><span>Author notes</span><ol><li><p>Ting Li and Hanqing Guo equal contributors.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Department of Gastroenterology & State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, China</p><p>Ting Li, Xiaodi Zhao, Yongquan Shi, Yuanyuan Lu, Sijun Hu, Yongzhan Nie, Daiming Fan & Kaichun Wu</p></li><li><p>Department of Gastroenterology, College of Medicine, Xi’an Central Hospital, Xi’an Jiaotong University, Xi’an, Shanxi, China</p><p>Hanqing Guo & Ying Song</p></li></ol><span>Authors</span><ol><li><span>Ting Li</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Hanqing Guo</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Ying Song</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xiaodi Zhao</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Yongquan Shi</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Yuanyuan Lu</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Sijun Hu</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Yongzhan Nie</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Daiming Fan</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Kaichun Wu</span>View author publications<p><span>You can also search for this author in</span><span>PubMed<span> </span>G","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"61 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653396","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":"Lactate accumulation induces H4K12la to activate super-enhancer-driven RAD23A expression and promote niraparib resistance in ovarian cancer","authors":"Bingfeng Lu, Shuo Chen, Xue Guan, Xi Chen, Yuping Du, Jing Yuan, Jielin Wang, Qinghua Wu, Lingfeng Zhou, Xiangchun Huang, Yang Zhao","doi":"10.1186/s12943-025-02295-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02295-w","url":null,"abstract":"Ovarian cancer is a gynecological malignancy with the highest recurrence and mortality rates. Although niraparib can effectively affect its progression, the challenge of drug resistance remains. Herein, niraparib-resistant ovarian cancer cell lines were constructed to identify the abnormally activated enhancers and associated target genes via RNA in situ conformation sequencing. Notably, the target gene RAD23A was markedly upregulated in niraparib-resistant cells, and inhibiting RAD23A restored their sensitivity. Additionally, abnormal activation of glycolysis in niraparib-resistant cells induced lactate accumulation, which promoted the lactylation of histone H4K12 lysine residues. Correlation analysis showed that key glycolysis enzymes such as pyruvate kinase M and lactate dehydrogenase A were significantly positively correlated with RAD23A expression in ovarian cancer. Additionally, H4K12la activated the super-enhancer (SE) of niraparib and RAD23A expression via MYC transcription factor, thereby enhancing the DNA damage repair ability and promoting the drug resistance of ovarian cancer cells. Overall, the findings of this study indicate that lactic acid accumulation leads to lactylation of histone H4K12la, thereby upregulating SE-mediated abnormal RAD23A expression and promoting niraparib resistance in ovarian cancer cells, suggesting RAD23A as a potential therapeutic target for niraparib-resistant ovarian cancer. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"55 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653397","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: Deciphering tumor microenvironment: CXCL9 and SPP1 as crucial determinants of tumor-associated macrophage polarity and prognostic indicators","authors":"Xinming Su, Chenhao Liang, Ruixiu Chen, Shiwei Duan","doi":"10.1186/s12943-025-02301-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02301-1","url":null,"abstract":"<p><b>Correction: Mol Cancer 23</b>,<b> 13 (2024)</b></p><p><b>https://doi.org/10.1186/s12943-023-01931-7</b></p><p>Following the publication of the original article [1], the authors realized that they used incorrect word when describing Fig. 1 in its caption, as follows: “A low CXCL9:SPP1 ratio defining TAM polarity suggests a TME enriched with immune activation and anti-tumor factors, pointing towards a promising prognosis. “. To rectify this error, they have prepared the correct versions as follows: “A high CXCL9:SPP1 ratio defining TAM polarity suggests a TME enriched with immune activation and anti-tumor factors, pointing towards a promising prognosis.”. The incorrect and correct Fig. 1 caption are provided below.</p><p> Incorrect Fig. 1 caption:</p><p> CXCL9:SPP1 polarity as an indicator of TME immune activity and prognosis in cancer patients. The CXCL9:SPP1 polarity could serve as an indicator of immune activity within the TME and may hold significance for patient prognosis. A low CXCL9:SPP1 ratio defining TAM polarity suggests a TME enriched with immune activation and anti-tumor factors, pointing towards a promising prognosis. Conversely, a low CXCL9:SPP1 ratio characterizing TAM polarity indicates the prevalence of immunosuppressive and tumor-promoting factors within the TME, correlating with a poorer prognosis. CXCL9:SPP1, CXCL9 and SPP1; TAMs, tumor-associated macrophages; TME, tumor microenvironment.</p><p> Correct Fig. 1 caption:</p><p> CXCL9:SPP1 polarity as an indicator of TME immune activity and prognosis in cancer patients. The CXCL9:SPP1 polarity could serve as an indicator of immune activity within the TME and may hold significance for patient prognosis. A high CXCL9:SPP1 ratio defining TAM polarity suggests a TME enriched with immune activation and anti-tumor factors, pointing towards a promising prognosis. Conversely, a low CXCL9:SPP1 ratio characterizing TAM polarity indicates the prevalence of immunosuppressive and tumor-promoting factors within the TME, correlating with a poorer prognosis. CXCL9:SPP1, CXCL9 and SPP1; TAMs, tumor-associated macrophages; TME, tumor microenvironment.</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Su X, Liang C, Chen R, et al. Deciphering tumor microenvironment: CXCL9 and SPP1 as crucial determinants of tumor-associated macrophage Polarity and prognostic indicators. Mol Cancer. 2024;23:13. https://doi.org/10.1186/s12943-023-01931-7.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China</p><p>Xinming Su, Chenhao Lia","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"9 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653393","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":"Shifting landscapes of gender equity in oncology journals: a decade of authorship trends","authors":"Hang Yi, Mingzhong Wan, Xu Ou-Yang, Yang Wang, Yan Wang, Yinyan Gao, Qihao Leng, Shuangping Zhang, Yousheng Mao, Guochao Zhang","doi":"10.1186/s12943-025-02286-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02286-x","url":null,"abstract":"Gender disparities persist in academic oncology, particularly in authorship and senior academic roles. This study evaluates trends in authorship gender representation over the past decade across top oncology journals, focusing on regional, journal-specific, and citation-based disparities. A cross-sectional analysis was conducted on 29,005 articles published between 2014 and 2023 in the top 20 oncology journals, identified through the Web of Science database. Author gender was determined using the NamSor tool. Temporal trends were analyzed using linear regression, and multivariate logistic regression identified factors contributing to gender disparities. Regional and citation analyses explored geographic variations and citation count differences. Among analyzed articles, 41.81% of first authors and 29.93% of last authors were female. Female first authorship showed a significant upward trend (P < 0.01), with gender parity projected by 2034, while parity for last authors is expected by 2055. Regional differences were notable, with North America and Europe leading in female representation. Certain journals, such as CA: A Cancer Journal for Clinicians and Molecular Cancer, exhibited higher female authorship proportions, while Journal of Clinical Oncology had the lowest. Citation analysis revealed female-authored articles received significantly fewer citations than male-authored ones (P < 0.01). Although female authorship in oncology journals has increased over the past decade, disparities remain, particularly in senior roles and citation impact. Addressing these issues requires targeted strategies, including mentorship programs, greater female representation in editorial boards, and institutional policies promoting gender equity.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"42 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635680","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":"o8G-modified circPLCE1 inhibits lung cancer progression via chaperone-mediated autophagy","authors":"Qingyun Zhao, Dunyu Cai, Haotian Xu, Yihong Gao, Ruirui Zhang, Xiaodong Zhou, Xingcai Chen, Sixian Chen, Jiaxi Wu, Wenyi Peng, Shengyi Yuan, Deqing Li, Gang Li, Aruo Nan","doi":"10.1186/s12943-025-02283-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02283-0","url":null,"abstract":"Lung cancer poses a serious threat to human health, but its molecular mechanisms remain unclear. Circular RNAs (circRNAs) are closely associated with tumour progression, and the important role of 8-oxoguanine (o8G) modification in regulating the fate of RNA has been gradually revealed. However, o8G modification of circRNAs has not been reported. We identified circPLCE1, which is significantly downregulated in lung cancer, and further investigated the o8G modification of circPLCE1 and the related mechanism in lung cancer progression. We identified differentially expressed circRNAs by RNA high-throughput sequencing and then conducted methylated RNA immunoprecipitation (MeRIP), immunofluorescence (IF) analysis, crosslinking immunoprecipitation (CLIP) and actinomycin D (ActD) assays to explore circPLCE1 o8G modification. The biological functions of circPLCE1 in vivo and in vitro were clarified via establishing a circPLCE1 silencing/overexpression system. Tagged RNA affinity purification (TRAP), RNA Immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays, and pSIN-PAmCherry-KFERQ-NE reporter gene were used to elucidate the molecular mechanism by which circPLCE1 inhibits lung cancer progression. This study revealed that reactive oxygen species (ROS) can induce circPLCE1 o8G modification and that AUF1 can mediate a decrease in circPLCE1 stability. We found that circPLCE1 significantly inhibited lung cancer progression in vitro and in vivo and that its expression was associated with tumour stage and prognosis. The molecular mechanism was elucidated: circPLCE1 targets the HSC70 protein, increases its ubiquitination level, regulates ATG5-dependent macroautophagy via the chaperone-mediated autophagy (CMA) pathway, and ultimately inhibits lung cancer progression. o8G-modified circPLCE1 inhibits lung cancer progression through CMA to inhibit macroautophagy and alter cell fate. This study provides not only a new theoretical basis for elucidating the molecular mechanism of lung cancer progression but also potential targets for lung cancer treatment. ROS induce circPLCE1 o8G modification, and AUF1 specifically recognizes o8G modification, thereby decreases circPLCE1 stability. circPLCE1 targets the HSC70 protein, increases its ubiquitination level, inhibits CMA activity, and promotes ATG5-dependent macroautophagy via the CMA pathway, altering the fate of tumour cells and ultimately inhibiting lung cancer progression. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"69 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635751","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":"IL-4 mediated TAP2 downregulation is a dominant and reversible mechanism of immune evasion and immunotherapy resistance in non-small cell lung cancer","authors":"Kishu Ranjan, Barani Kumar Rajendran, Imad Ud Deen, Adrien Costantini, Miguel Lopez de Rodas, Shruti S. Desai, Frankie Scallo, Nicole Gianino, Soldano Ferrone, Kurt A. Schalper","doi":"10.1186/s12943-025-02276-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02276-z","url":null,"abstract":"Resistance to both naturally occurring anti-cancer immunity and to immunotherapy is common in patients with aggressive non-small cell lung cancer (NSCLC). Recent studies indicate a role of loss of the HLA class-I antigen presentation machinery (APM) protein β-2-microglobulin in acquired resistance to immune checkpoint blockers. However, the mechanisms, functional consequences and therapeutic potential of APM defects in NSCLC remain poorly understood. Using multiplexed immunofluorescence, we spatially mapped CD8+ effector Tumor-Infiltrating Lymphocytes (TILs) and the APM components TAP1 and TAP2 in 819 baseline/pre-treatment NSCLCs from patients treated with and without PD-1 axis blockers in 4 independent cohorts. The impact of TAP1/2 silencing in lung cancer cells using siRNAs and CRISPR/Cas9 was studied using transcriptomic analysis, phosphoprotein arrays, ATAC-sequencing, measurement of surface HLA-peptide complexes and in vitro tumor-antigen specific T-cell killing. We established autologous co-cultures of tumor and immune cells from primary human NSCLCs to study the functional impact of IL4Rα and/or PD-1 blockade using monoclonal antibodies. A high-throughput drug screen supported the identification of compounds able to increase TAP2 expression in NSCLC cells. We identified cancer cell selective TAP2 protein downregulation in 42.4% of treatment naïve NSCLCs associated with reduced sensitivity to immune checkpoint blockers. TAP1 downregulation occurred in 24.4% of lung tumors without survival impact. Silencing of TAP2 in lung cancer cells altered key intracellular immunomodulatory pathways, limited sensitivity to proinflammatory cytokines, reduced the levels of surface peptide-HLA complexes and protected malignant cells from tumor antigen-specific T-cell killing via SOCS1 upregulation. TAP2 loss in human NSCLCs was associated with reduced TAP2 promoter chromatin accessibility and elevated IL-4 IL-4 expression. Treatment with IL-4 reduced TAP2 levels and the chromatin accessibility of the TAP2 gene promoter in NSCLC cells and reproduced all the functional consequences of TAP2 loss. In intact human NSCLC, IL-4 IL-4 transcripts were detected in intratumoral myeloid cells and IL-4Rα blockade increased human NSCLC cell killing by autologous TILs. Epigenetic modulators and other drugs with known anti-cancer activity increased TAP2 expression and its function in lung cancer cells. Our study reveals previously unrecognized functions of TAP2 beyond antigen presentation and establishes a reversible multi-cellular axis mediating adaptive immune evasion and immunotherapy resistance with clinical potential.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635681","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}