Molecular Cancer最新文献

{"title":"Integrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune response","authors":"Yiyi Chen, Ningning Zhao, Lingna Xu, Xiya Jia, Fang Liu, Jian Huang, Xuhua Li, Yunfei Wang, Chuanxi Lai, Yanbin Shen, Fei Wang, Yiming Lv, Xuefeng Huang, Fan Zhang, Hongcang Gu, Sheng Dai","doi":"10.1186/s12943-025-02359-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02359-x","url":null,"abstract":"Colorectal cancer (CRC) is a major global health concern, characterized by high morbidity and mortality rates. CRC progression involves intricate molecular networks that remain incompletely understood. In this study, we conducted an integrative multi-omics analysis of transcriptomic, proteomic, and metabolomic profiles from CRC tissues and matched normal adjacent tissues (NATs). Our analysis revealed 1,394 differentially expressed long non-Coding RNAs (lncRNAs), 2,788 genes, 548 proteins, and 91 metabolites. A significant interaction network comprising 22 lncRNAs, 14 mRNAs/proteins, and 9 metabolites was identified, among which lncRNA 60967.1 emerged as a pivotal regulator. Functional validation demonstrated that lncRNA 60967.1 is markedly downregulated in CRC cell lines and patient tissues. Overexpression of lncRNA 60967.1 restored expression of the tumor suppressor PLCD4 and increased levels of all-trans retinoic acid (ATRA). This modulation enhanced IFN-γ-induced apoptosis and increased expression of the IFN-γ receptor subunit IFNGR1, thereby partially reversing IFN-γ resistance. In murine models, lncRNA 60967.1 overexpression promoted immune cell infiltration and synergized with anti–PD-1 therapy to inhibit tumor growth. Collectively, our findings uncover a novel lncRNA-mRNA/protein-metabolite network, the lncRNA 60967.1-PLCD4-ATRA axis, that plays a critical role in CRC progression and immune modulation, offering promising therapeutic targets for improved treatment efficacy. Colorectal cancer (CRC) is characterized by substantial genetic and epigenetic heterogeneity, underscoring the need for novel therapeutic targets. While immunotherapy has led to significant advancements in cancer treatment, approximately 85% of CRC patients exhibit resistance due to different genetic and epigenetic features. Multi-omics approaches, which integrate data across genomic, proteomic, and metabolomic layers, have emerged as powerful tools for elucidating disease mechanisms. In this study, we conducted multi-omics analyses on tumor and adjacent normal tissues from 13 CRC patients. Complementary in vitro and in vivo experiments demonstrated that lncRNA 60967.1 regulates the PLCD4/ATRA axis and modulates the immune response to anti-PD-1 therapy, thereby promoting CRC progression. Our findings reveal a novel regulatory network involving lncRNA, PLCD4, and ATRA, providing a potential new target for CRC therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"45 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228829","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":"GUIDE: a prospective cohort study for blood-based early detection of gastrointestinal cancers using targeted DNA methylation and fragmentomics sequencing","authors":"Ao Huang, De-Zhen Guo, Zhi-Xi Su, Yun-Shi Zhong, Liang Liu, Zhi-Guo Xiong, Dong-Li He, Bin Yan, Quan-Lin Li, Zhen Feng, Wen-Quan Wang, Pin-Xiang Lu, Meng-Jiang He, Zhi-Peng Qi, Qi Guo, Jian-Wen Cheng, Shi-Yu Zhang, Wei Guo, Qing Li, Guo-Yong Lin, Hui-Chuan Sun, Shuang-Jian Qiu, Qi-Ye He, Jia Fan, Ajay Goel, Rui Liu, Gang Jin, Xin-Rong Yang, Jian Zhou","doi":"10.1186/s12943-025-02367-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02367-x","url":null,"abstract":"Gastrointestinal (GI) cancers are among the most prevalent and lethal malignancies worldwide. Early, non-invasive detection is essential for timely intervention and improved survival. To address this clinical need, we developed GutSeer, a blood-based assay combining DNA methylation and fragmentomics for multi-GI cancer detection. Genome-wide methylome profiling identified 1,656 markers specific to five major GI cancers and their tissue origins. Based on these findings, we designed GutSeer, a targeted bisulfite sequencing panel, which was trained and validated using plasma samples from 1,057 cancer patients and 1,415 non-cancer controls. The locked model was blindly tested in an independent cohort of 846 participants, encompassing both inpatient and outpatient settings across five hospitals. In the validation cohort, GutSeer achieved an area under the curve (AUC) of 0.950 [95% Confidence Interval (CI): 0.937–0.962] for cancer detection, with 82.8% sensitivity (95% CI: 79.5–86.0) and 95.8% specificity (95% CI: 94.3–97.2). It detected 92.2% of colorectal, 75.5% of esophageal, 65.3% of gastric, 92.9% of liver, and 88.6% of pancreatic cancers. The independent test cohort included 198 early-stage cancers (stage I/II, 66.4%) and 63 advanced precancerous lesions. GutSeer maintained robust performance, with 81.5% sensitivity (95% CI: 77.1–85.9) for GI cancers and 94.4% specificity (95% CI: 92.4–96.5). It also demonstrated the ability to detect advanced precancerous lesions in the colorectum, esophagus, and stomach as a single, non-invasive blood test. By integrating DNA methylation and fragmentomics into a compact panel, GutSeer outperformed genome-wide sequencing in both accuracy and clinical applicability. Its high sensitivity for early-stage GI cancers and practicality as a non-invasive assay highlights its potential to revolutionize early cancer detection and improve patient outcomes. ClinicalTrials.gov identifier: NCT05431621.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"38 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144218737","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":"Precision nanomedicine: navigating the tumor microenvironment for enhanced cancer immunotherapy and targeted drug delivery","authors":"Hussein Sabit, Timothy M. Pawlik, Faisal Radwan, Mohamed Abdel-Hakeem, Shaimaa Abdel-Ghany, Al-Hassan Soliman Wadan, Mokhtar Elzawahri, Ahmed El-Hashash, Borros Arneth","doi":"10.1186/s12943-025-02357-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02357-z","url":null,"abstract":"Cancer treatment has been revolutionized by immunotherapy and nanomedicine, offering innovative strategies to overcome the tumor microenvironment (TME) complexities. However, challenges such as therapeutic resistance, off-target effects, and immune suppression necessitate advanced delivery systems and combination approaches. Recent advancements in nanoparticle-based therapies, biomimetic platforms, and personalized immunotherapy provide promising solutions to enhance therapeutic efficacy while minimizing systemic toxicity. This review explores recent nanoparticle-mediated immunotherapy developments, highlighting strategies to optimize drug delivery, remodel the TME, and improve patient-specific treatment outcomes. A comprehensive review of recent literature focused on nanoparticle-based drug delivery, stimuli-responsive systems, biomimetic nanoplatforms, and personalized immunotherapy approaches. The effectiveness of combination therapies integrating physical and immunological strategies was also analyzed. Nanoparticle-mediated immunotherapy enables precise targeting and controlled drug release, significantly improving therapeutic outcomes. Biomimetic nanoplatforms enhance immune modulation and drug bioavailability, while personalized immunotherapy, guided by predictive biomarkers, tailors treatment to individual patients. Advanced nanomedicine strategies, including TME remodeling, targeted genome editing, and combination immunotherapies, offer promising avenues for overcoming limitations in conventional cancer treatments. Future research should optimize nanoformulations, integrate multi-modal treatment strategies, and refine biomarker-driven personalization to enhance clinical outcomes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"135 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201899","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":"Establishing 3D organoid models from patient-derived conditionally reprogrammed cells to bridge preclinical and clinical insights in pancreatic cancer","authors":"Jin Su Kim, Chan Hee Park, Eunyoung Kim, Hee Seung Lee, Jinyoung Lee, Jeehoon Kim, Eun Hee Kam, Sanghee Nam, Moon Jae Chung, Jeong Youp Park, Seung Woo Park, Sangwoo Kim, Galam Leem, Seungmin Bang","doi":"10.1186/s12943-025-02374-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02374-y","url":null,"abstract":"Pancreatic cancer is a highly lethal malignancy with limited treatment response. Despite advancements in treatment, systemic chemotherapy remains the primary therapeutic approach for over 80% of patients, with no established biomarkers to guide drug selection. Traditional two-dimensional (2D) culture models fail to replicate the tumor microenvironment, necessitating the development of more advanced models, such as three-dimensional (3D) organoid models. We established 3D organoid cultures using patient-derived conditionally reprogrammed cell (CRC) lines, originally cultured under 2D conditions. These CRC organoids were developed using a Matrigel-based platform without organoid-specific medium components to preserve the intrinsic molecular subtypes of the cells. Morphological, molecular, and drug sensitivity analyses were performed to compare the clinical responses of 3D CRC organoids with those of their 2D counterparts and clinical responses. The 3D CRC organoids retained the molecular characteristics, transcriptomic and mutational profiles of the parental tumors and displayed distinct morphologies corresponding to cancer stages and differentiation. Drug response profiling of gemcitabine plus nab-paclitaxel (Abraxane) and FOLFIRINOX demonstrated that the 3D organoids more accurately mirrored patient clinical responses than the 2D cultures. Notably, the IC50 values for the 3D organoids were generally higher, reflecting the structural complexity and drug penetration barriers observed in vivo. Matrigel-based 3D organoid culture models provide a robust platform for pre-clinical drug evaluation, overcoming the limitations of 2D models. Although time- and resource-intensive, integrating both 2D and 3D platforms enables efficient initial screening and validation. This approach holds promise for identifying predictive biomarkers and advancing precision medicine in pancreatic cancer treatment.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"26 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201956","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":"Reprogrammed immuno-metabolic environment of cancer: the driving force of ferroptosis resistance","authors":"Sramana Bhowmick, Saptak Banerjee, Viji Shridhar, Susmita Mondal","doi":"10.1186/s12943-025-02337-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02337-3","url":null,"abstract":"Ferroptosis, the non-apoptotic, iron-dependent form of cell death is an unavoidable outcome and byproduct of cellular metabolism. Reactive oxygen species generation during metabolic activities transcends to Fe2+-induced lipid peroxidation, leading to ferroptosis. Cancer cells being highly metabolic are more prone to ferroptosis. However, their neoplastic nature enables them to bypass ferroptosis and become ferroptosis-resistant. The capability of cancer cells to reprogram its metabolic activities is one of its finest abilities to abort oxidative damage, and hence ferroptosis. Moreover, the reprogrammed metabolism of cancer cells, also associates with the radical trapping antioxidant systems to enhance the scavenging of ferroptosis and thereby tumor progression. Additionally, the TME, which is an inevitable part and regulator of carcinogenesis, presents an intricate cooperation with tumor metabolism to build an immuno-metabolic environment to regulate the sustenance of cell proliferation and survival. This review focuses on the current understanding of ferroptosis in carcinogenesis and its resistance acquired by cancer cells via several modulators including the radical trapping antioxidant systems, the reprogrammed metabolism, the TME, and intertwined role of cancer metabolism and tumor immunity. The reprogrammed metabolism section further comprehends the functional role of lipids, iron and glucose metabolism against ferroptosis defense separately. The affiliation of TME in ferroptosis regulation is further sectioned with reference to different immune cells present within the TME such as tumor-associated macrophages, tumor-infiltrating neutrophils, myeloid-derived suppressor cells, T-cells, natural killer cells, dendritic cells, and B-cells, modifying the TME in both pro and anti-tumorigenic manner. Subsequently, this review also discusses the convergence of immuno-metabolic environment in ferroptosis regulation, and eventually brings up research gaps in this context providing consequential and significant questions to explore for better understanding of the immuno-metabolic environment’s role in driving ferroptosis resistance for anti-cancer treatment progress.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"19 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201884","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":"Current AI technologies in cancer diagnostics and treatment","authors":"Ashutosh Tiwari, Soumya Mishra, Tsung-Rong Kuo","doi":"10.1186/s12943-025-02369-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02369-9","url":null,"abstract":"Cancer continues to be a significant international health issue, which demands the invention of new methods for early detection, precise diagnoses, and personalized treatments. Artificial intelligence (AI) has rapidly become a groundbreaking component in the modern era of oncology, offering sophisticated tools across the range of cancer care. In this review, we performed a systematic survey of the current status of AI technologies used for cancer diagnoses and therapeutic approaches. We discuss AI-facilitated imaging diagnostics using a range of modalities such as computed tomography, magnetic resonance imaging, positron emission tomography, ultrasound, and digital pathology, highlighting the growing role of deep learning in detecting early-stage cancers. We also explore applications of AI in genomics and biomarker discovery, liquid biopsies, and non-invasive diagnoses. In therapeutic interventions, AI-based clinical decision support systems, individualized treatment planning, and AI-facilitated drug discovery are transforming precision cancer therapies. The review also evaluates the effects of AI on radiation therapy, robotic surgery, and patient management, including survival predictions, remote monitoring, and AI-facilitated clinical trials. Finally, we discuss important challenges such as data privacy, interpretability, and regulatory issues, and recommend future directions that involve the use of federated learning, synthetic biology, and quantum-boosted AI. This review highlights the groundbreaking potential of AI to revolutionize cancer care by making diagnostics, treatments, and patient management more precise, efficient, and personalized. This graphical abstract schematically illustrates the progressive role of artificial intelligence in the cancer treatment continuum. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"7 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193251","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":"Nuclear receptors as novel regulators that modulate cancer radiosensitivity and normal tissue radiotoxicity","authors":"Xiaochen Meng, Xiaoqian Li, Yi Gao, Shuyu Zhang","doi":"10.1186/s12943-025-02362-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02362-2","url":null,"abstract":"Nuclear receptors (NRs) are a superfamily of transcription factors that are involved in various pathophysiological processes. The human genome contains 48 types of nuclear receptors, including steroid hormone receptors (e.g., estrogen receptor [ER] and vitamin D receptor [VDR]), nonsteroid hormone receptors (e.g. peroxisome proliferator-activated receptor [PPAR] and retinoic acid receptor [RAR]), and orphan nuclear receptors (e.g. neuron‐derived clone 77 [Nur77] and testicular nuclear receptor 4 [TR4]) and certain nuclear receptors are specifically overexpressed in tumor cells or surrounding normal tissues. Radiotherapy is one of the main methods of tumor treatment, but radioresistance in tumors and radiotoxicity to normal tissues strongly affect radiotherapy efficacy. Accumulating evidence has indicated the critical role of nuclear receptor modulators (including agonists and antagonists) as promising radiosensitizers in radiotherapy through various mechanisms. In addition, several nuclear receptors and their agonists alleviate normal tissue toxicity during radiotherapy. Thus, nuclear receptors serve as novel targets for tumor radiosensitization and for protecting of normal tissues from radiation damage. This review summarizes the research progress of nuclear receptors and highlights a promising synergistic strategy in radiotherapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"2 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176609","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":"Loss of TACC2 impairs chemokine CCL3 and CCL4 expression and reduces response to anti-PD-1 therapy in soft tissue sarcoma","authors":"Jing Yang, Xiuxia Lu, Qiyan Cai, Mengmeng Liu, Tianliang Xia, Dongchun Hong, Liyuan Le, Xinke Zhang, Xing Zhang","doi":"10.1186/s12943-025-02354-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02354-2","url":null,"abstract":"Soft tissue sarcoma (STS) is a rare, heterogeneous malignancy with limited treatment options for metastatic disease. Despite advances in immunotherapy, including PD-1 inhibitors, clinical outcomes remain suboptimal, highlighting the need for novel biomarkers and therapeutic strategies. This study investigated the role of TACC2 in STS, focusing on its impact on the immune microenvironment and immunotherapy response. Whole-exome sequencing was performed to characterize TACC2-related genomic alterations in STS cohorts, complemented by immunohistochemistry for protein-level validation. Mechanistic insights were obtained through chromatin immunoprecipitation (ChIP) and co-immunoprecipitation assays, focusing on TACC2’s interaction with the NuRD/CoREST complex. The efficacy of anti-PD-1 therapy was evaluated in TACC2-overexpressing mouse models, and clinical relevance was analyzed using patient survival and treatment response data. TACC2 acted as a tumor suppressor in STS, with low expression associated with poor overall survival. Mechanistically, TACC2 enhanced CCL3 and CCL4 transcription, promoting CD8 + T cell infiltration by inhibiting NuRD/CoREST nuclear translocation. In vivo, TACC2 overexpression synergized with PD-1 blockade therapy, leading to a significant reduction in tumor volume and prolonged survival. Clinically, high TACC2 expression was associated with improved responses to immunotherapy. In conclusion, TACC2 is an important regulator of the immune response in STS, functioning as a tumor suppressor and a modulator of response to PD-1 blockade. Its role in modulating chemokine expression and CD8 + T cell infiltration highlights its potential as a therapeutic target and predictive biomarker for STS immunotherapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"60 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176542","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 BATF2-RGS2 axis reduces T-cell exhaustion and restores anti-tumor immunity","authors":"Xuyu Gu, Chanchan Gao, Xiangyu Su, Yaoyao Zhu, Qiyu Fang, Jia Yu, Ziming Wang, Deping Zhao, Wentian Zhang","doi":"10.1186/s12943-025-02351-5","DOIUrl":"https://doi.org/10.1186/s12943-025-02351-5","url":null,"abstract":"This study aims to investigate the role of RGS2 in immune regulation in lung cancer (LC) and explore the regulatory relationship between RGS2 and BATF2 in modulating T cell exhaustion and tumor immune evasion. Single-cell transcriptome-based analysis was performed to identify CD8+ T-cell profiles and regulatory factors in six LC patients receiving neoadjuvant PD-1 blockade therapy. Mouse 3LL cells or murine tumor organoid models were transplanted into wild-type, RGS2 knock-out (RGS2−/−), or BATF2 knock-out (BATF2−/−) mice to analyze the effects of RGS2 and BATF2 on tumor growth, metastasis, and immune cell infiltration. CD8+ from these mice were isolated and co-cultured with cancer cells to analyze T cell cytotoxicity in vitro. The transcriptional regulation of RGS2 by BATF2 was analyzed using luciferase reporter assays. RGS2 was highly expressed in CD8+ T-exhausted (Tex) cells and was associated with pro-inflammatory pathways. High RGS2 expression predicted poor clinical outcomes and limited response to PD-1/PD-L1 blockade therapy. In RGS2−/− mice, tumor metastasis and angiogenesis were suppressed, CD8+ effector T cells were enhanced, and T cell exhaustion markers were reduced. BATF2 was identified as a key transcriptional regulator of RGS2, promoting T cell exhaustion through inhibition of CXCL13 secretion. Knockdown of BATF2 or RGS2 impaired lung cancer cell proliferation and enhanced sensitivity to NK cell-mediated cytotoxicity in vitro. In BATF2−/− mice, the populations of immune active CD8+ T cells were increased, while exhausted T cells were reduced, leading to improved anti-tumor immune responses. RGS2, regulated by BATF2, plays a critical role in driving T cell exhaustion and tumor immune evasion in LC. Targeting the BATF2-RGS2 axis may enhance the effectiveness of immunotherapy by reversing T cell exhaustion and improving anti-tumor immunity.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"147 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176545","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":"Co-targeting of epigenetic regulators and BCL-XL improves efficacy of immune checkpoint blockade therapy in multiple solid tumors","authors":"Yaiza Senent, Vicente Fresquet, Victoria Jiménez, Karmele Valencia, Francisco Exposito, Patxi San Martín-Úriz, Gracián Camps, Eva Fernández-Pierola, Borja Ruiz-Fernández de Córdoba, Marisol González-Huarriz, Ibon Tamayo, Ana Remírez, Haritz Moreno, Diego Serrano, Daniel Ajona, Marta M. Alonso, Fernando Lecanda, Antonio Pineda-Lucena, Felipe Prósper, Miguel F. Sanmamed, Alfonso Calvo, Jose A. Martinez-Climent, Ruben Pio","doi":"10.1186/s12943-025-02352-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02352-4","url":null,"abstract":"Epigenetic modulators in combination with proapoptotic drugs have become the standard of care treatment in hematological malignancies. Conversely, these combinations have failed to demonstrate clinical efficacy in solid tumors. To address this discrepancy, we conducted a comprehensive analysis of the anti-tumor activity of epigenetic inhibitors in combination with BH3 mimetics that block anti-apoptotic proteins BCL-XL, BCL2 or MCL1 in a large set of solid tumor cell lines derived from patients and mouse models. Treatment with epigenetic drugs targeting DNA methyltransferase, histone methyltransferase, and histone deacetylase enzymes in combination with a BCL-XL inhibitor resulted in marked synergistic in vitro responses both in human and mouse solid tumor cell lines. This unique BCL-XL dependency was in clear contrast to hematological malignancies, which are largely dependent on BCL2 or MCL1 inhibition under epigenetic drug treatment. Mechanistically, co-targeting of epigenetic regulators and BCL-XL induced expression of endogenous retroelements that led to immunogenic cell death. We thus hypothesized that this response may sensitize tumor cells to immune checkpoint blockade (ICB). Accordingly, treatment with a triple combination of epigenetic and BCL-XL inhibitors with an anti-PD-1 monoclonal antibody in vivo reduced tumor growth and prolonged overall survival in a panel of murine syngeneic and orthotopic models of lung, colorectal and breast carcinomas, melanoma, and glioblastoma, as well as in an immunocompetent human colon cancer model. Using flow cytometry and single-cell RNA sequencing of the tumor microenvironment, we found that the broad activity of the triple therapy relied on the expansion of T and NK cells with cytotoxic potential, an increase in the M1/M2 macrophage ratio, and a reduction of immunosuppressive Treg cells, dendritic cells, and B lymphocytes. In conclusion, we report a novel regimen combining epigenetic and BCL-XL inhibitors with ICB that produces potent anti-tumor responses in multiple preclinical models of solid tumors.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"26 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176546","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}