Molecular Cancer最新文献

{"title":"Neurotransmitters: an emerging target for therapeutic resistance to tumor immune checkpoint inhibitors","authors":"Jiyuan Yang, Yu Wu, Xinhui Lv, Sicong Liu, Ziwen Yuan, Yafang Chen, Xiangyu Ding, Zhong Li, Xudong Wang","doi":"10.1186/s12943-025-02413-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02413-8","url":null,"abstract":"The critical role of neurotransmitters in the resistance to tumor immune checkpoint inhibitor (ICI) is becoming increasingly significant in therapeutic contexts. ICIs work by enhancing antitumor immunity through the blockade of the PD-1/PD-L1 and CTLA-4 pathways. However, only 20% of patients experience durable efficacy, and the challenge of drug resistance limits the clinical application of these therapies. Drug resistance is closely linked to various factors within the tumor microenvironment, including the distribution of tumor-infiltrating lymphocytes, the function of tumor-associated macrophages, low expression levels of PD-L1, variations in tumor mutational burden, dysregulation of antigen presentation, and both genetic and epigenetic changes in tumor cells. In recent years, the importance of the neural-immune axis has gained attention. Abnormal nerve fiber growth or irregular secretion of neurotransmitters can contribute to immune evasion. Neurotransmitters such as dopamine, norepinephrine, and serotonin influence the tumor microenvironment by regulating the expression of immune checkpoints and the function of immune cells, which can promote immune escape. As a result, therapeutic strategies that target neurotransmitters and their receptors hold promise for overcoming resistance to ICIs. These strategies may significantly enhance the efficacy of ICIs and pave the way for new approaches in cancer therapy. This article reviews the relevant mechanisms and proposes potential therapeutic strategies, offering new insights for the field.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"290 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819154","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":"Integrating neuroscience and oncology: neuroimmune crosstalk in the initiation and progression of digestive system tumors","authors":"Haonan Sun, Tao Wang, Xiangyan Jiang, Mingdou Li, Xiaoe He, Yong Ma, Xiangkai Li, Weilin Jin, Zuoyi Jiao","doi":"10.1186/s12943-025-02412-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02412-9","url":null,"abstract":"Recent global data show that cancers of the digestive system are responsible for approximately one-third of all cancer-related deaths worldwide, underscoring the urgent need for innovative therapeutic strategies. In this context, emerging findings from neuroscience may unveil new avenues for tackling this pressing clinical problem. Over the past few years, rapid progress in cancer neuroscience has increasingly underscored the contribution of the nervous system to the development and progression of digestive tract tumors. Research has shown that the specialized neural network of the gastrointestinal tract establishes a framework for reciprocal interactions with digestive tract tumors. On this anatomical foundation, our review delves into the functional significance of these interactions, emphasizing the bidirectional regulatory pathways between the nervous system and tumor cells during disease progression and highlighting their intricate crosstalk with the immune microenvironment. In particular, it maps the molecular pathways by which both the central and peripheral nervous systems (PNS) modulate tumor initiation and progression. Moreover, it explains how neurotransmitters and neuroendocrine mediators drive tumor expansion through the activation of canonical oncogenic signaling cascades and the remodeling of the immunosuppressive microenvironment. This review seeks to elucidate the molecular underpinnings of neuro-immune-tumor crosstalk and to synthesize the latest neural-targeted therapeutic approaches. It also examines the principal obstacles that are impeding the clinical implementation of these interventions. By presenting an integrated overview, this work serves as a robust resource to inform future studies on neurobiological mechanisms and the development of novel therapies for gastrointestinal malignancies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"16 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812841","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":"CircRNA aptamer targets IGF2BP2 to overcome acquired BETi resistance","authors":"Christophe Nicot","doi":"10.1186/s12943-025-02423-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02423-6","url":null,"abstract":"<p>Bromodomain-and-extra-terminal-domain (BET) proteins are critical epigenetic readers that recognize acetylated histones to regulate transcription activation [1]. Their crucial role in activating oncogene expression (particularly c-MYC) has positioned BET inhibitors (BETi) as promising epigenetic therapeutics for refractory malignancies, including triple-negative breast cancer (TNBC). However, the clinical efficacy of BETi has been substantially limited by the rapid emergence of drug resistance, evidenced by the termination of approximately 50% of BETi monotherapy trials for solid tumors [2]. This therapeutic challenge underscores the urgent need for innovative strategies to overcome BETi resistance. A recent breakthrough study by Guo et al. identified a circular RNA (circRNA) named BISC that overcomes acquired BETi resistance by specifically targeting the RNA-binding protein IGF2BP2 to suppress <i>c-MYC</i> mRNA translation [3]. These findings not only reveal a novel BETi resistance mechanism but also highlight the potential of circRNA-based therapies to address the critical challenge of drug resistance in TNBC.</p><p>Drug resistance represents a major limitation, primarily emerging through either target-specific modification (e.g. altered target expression or resistance-conferring mutations) or the compensatory activation of alternative survival pathways. This challenge is particularly pronounced for epigenetic inhibitors like BETi, where genome-wide transcriptional reprogramming can simultaneously activate both therapeutic and resistance pathways. In prostate cancer, intrinsic BETi resistance stems from ubiquitin system dysregulation, characterized by diminished SPOP-mediated degradation [4] or enhanced DUB3-mediated stabilization of BET proteins [5]. Similarly, non-small cell lung cancer (NSCLC) exhibits BETi resistance in <i>LKB1</i>-deficient specimens [6] or through BCL6/mTOR pathway activation following BRD3 inhibition [7]. Although <i>c-myc</i> functions as a primary BRD4 effector in BETi-sensitive malignancies such as TNBC [8] and acute myeloid leukemia (AML) [9], its reactivation following prolonged BETi exposure drives acquired drug resistance. Notably, Guo et al. recently identified a novel resistance mechanism in TNBC, where IGF2BP2-mediated translational control sustains c-MYC expression independent of transcriptional regulation (through β-catenin, GLI2, or MED1 activation) or protein stability [3] (Fig. 1). These findings reveal enhanced c-MYC translation as a previously underappreciated cause of epigenetic therapy resistance.</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-025-02423-6/MediaObjects/12943_2025_2423_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"587\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"260 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812898","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":"Cellular senescence in cancer: from mechanism paradoxes to precision therapeutics","authors":"Tiejun Feng, Fuda Xie, Leo M.Y. Lee, Zhiqiang Lin, Yifan Tu, Yang Lyu, Peiyao Yu, Jialin Wu, Bonan Chen, Ge Zhang, Gary M.K. Tse, Ka Fai To, Wei Kang","doi":"10.1186/s12943-025-02419-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02419-2","url":null,"abstract":"Cellular senescence is a double-edged sword in cancer biology, functioning as both a tumor-suppressive mechanism and a driver of malignancy. Initially, senescence acts as a protective barrier by arresting the proliferation of damaged or oncogene-expressing cells via pathways such as oncogene-induced senescence and the DNA damage response. However, persistent senescence-associated secretory phenotype and metabolic reprogramming in senescent cells create a pro-inflammatory, immunosuppressive tumor microenvironment, fueling cancer progression, therapy resistance, and metastasis. This comprehensive review systematically examines the molecular mechanisms of senescence across diverse cancers, spanning digestive, reproductive, urinary, respiratory, nervous, hematologic, endocrine, and integumentary systems, and elucidates its context-dependent roles in tumor suppression and promotion. We highlight groundbreaking therapeutic innovations, including precision senolytics, senomorphics, and combinatorial strategies integrating immunotherapy, metabolic interventions, and epigenetic modulators. The review also addresses microenvironment remodeling and cutting-edge technologies for dissecting senescence heterogeneity, epigenetic clocks for biological age prediction, and microbiome engineering to modulate senescence. Despite their promise, challenges such as off-target effects, biomarker limitations, and cellular heterogeneity underscore the need for precision medicine approaches. Finally, we propose future directions to harness senescence as a dynamic therapeutic target, offering transformative potential for cancer treatment.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"35 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797079","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":"Metabolic checkpoints in immune cell reprogramming: rewiring immunometabolism for cancer therapy","authors":"Yingying Lv, Zongshang Li, Shutong Liu, Zhaokai Zhou, Jinling Song, Yuhao Ba, Siyuan Weng, Anning Zuo, Hui Xu, Peng Luo, Quan Cheng, Chuhan Zhang, Jingyuan Ning, Yukang Chen, Yuyuan Zhang, Zaoqu Liu, Xinwei Han","doi":"10.1186/s12943-025-02407-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02407-6","url":null,"abstract":"Immune cell metabolism plays a pivotal role in regulating cellular proliferation, differentiation, and functional responses, collectively shaping immune responses within the tumor microenvironment (TME). Recent advancements increasingly highlight diverse metabolic phenotypes of immune cells and their complex interplay with tumor dynamics. Immune cell metabolism exhibits remarkable plasticity, enabling metabolic networks to finely tune immune cell behaviors in response to external stimuli. Furthermore, a strong correlation between metabolic profiles and immune cell fate, activation, and function has been repeatedly delineated in immunometabolism. Consequently, targeting the metabolic networks, referred to as metabolic checkpoints, to reprogram immune cell phenotypes and bolster antitumor immunity holds significant promise for clinical translation. This review summarizes the latest developments in multifaceted metabolic checkpoints, with a focus on how metabolic checkpoints modulate immunological consequences and cancer progression. Lastly, potential strategies for targeting metabolic checkpoints are explored to inspire innovative approaches in immunotherapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"724 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144763202","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":"Traditional Chinese medicine in the treatment of breast Cancer","authors":"Peng Song, Tongtong Liu, Yinfang Zhang, Tingting Shao, Rongkun Li, Chaoxia An, Lu-Qi Cao, Zhe-Sheng Chen, Wenjing Guo, Dongzhu Duan","doi":"10.1186/s12943-025-02416-5","DOIUrl":"https://doi.org/10.1186/s12943-025-02416-5","url":null,"abstract":"Breast cancer (BC) is the most commonly diagnosed malignancy among women globally. While treatments such as chemotherapy and endocrine therapy have contributed to improving survival rates, there remains a critical need for more effective therapeutic options. Traditional Chinese Medicine (TCM), with a history spanning thousands of years, has long been utilized in the management of BC. This includes a wide range of practices, such as the use of traditional compound prescriptions, Chinese medicine monomers and extracts, acupuncture, moxibustion, and mind-body therapies. This review summarizes the brief history and experience of TCM in treating BC refer to numerous ancient Chinese medical texts, and explores the role of various TCM approaches in the treatment of BC, providing an in-depth analysis of their potential benefits. Additionally, it addresses the current limitations and challenges in researching TCM’s effectiveness for BC. Through this review, we aim to offer valuable insights into how TCM can complement conventional therapies and enhance outcomes for patients with BC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"1 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756360","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 FGFR4 abrogates HNF1A-driven metastasis in pancreatic ductal adenocarcinoma","authors":"Katherine J. Crawford, Kennedy S. Humphrey, Eduardo Cortes, Jianxin Wang, Vishnu Kumarasamy, Yin Wan, Mark D. Long, Michael E. Feigin, Agnieszka K. Witkiewicz, Karen M. Mann, Erik S. Knudsen, Ethan V. Abel","doi":"10.1186/s12943-025-02408-5","DOIUrl":"https://doi.org/10.1186/s12943-025-02408-5","url":null,"abstract":"We previously identified an oncogenic role for the transcription factor HNF1A in pancreatic ductal adenocarcinoma (PDAC). However, the role of HNF1A in the metastatic progression of PDAC remains unknown and targeting modalities for HNF1A-dependent phenotypes have yet to be identified. Transwell chambers were used to assess the effects of HNF1A and FGFR4 modulation on the migration and invasion of ATCC and patient-derived PDAC cells in vitro. An intrasplenic injection xenograft model was used to evaluate the impact of HNF1A knockdown and overexpression on metastatic tumor burden. Single-cell RNA sequencing (scRNA-seq), tissue microarray (TMA) data, and UMAP spatial profiling were used to identify FGFR4 as an HNF1A target gene upregulated in metastatic cells. RNAi and two FGFR4 inhibiting modalities (H3B-6527 and U3-1784) were utilized to demonstrate the efficacy of FGFR4 inhibiting agents at reducing HNF1A-driven metastasis. Knockdown of HNF1A significantly decreases and HNF1A overexpression significantly increases PDAC cell migration and invasion. In vivo studies show that HNF1A knockdown significantly abrogates metastasis, while overexpression significantly promotes metastasis. scRNA-seq shows that FGFR4 is upregulated in metastatic PDAC cells and staining for HNF1A and FGFR4 in a PDAC TMA reveals significant correlation between HNF1A and FGFR4 in PDAC patients. Further, knockdown and inhibition of FGFR4 significantly decreases HNF1A-mediated cell migration and invasion, and blocks HNF1A-driven metastasis in vivo. These findings demonstrate that HNF1A drives PDAC metastasis via upregulation of FGFR4, and FGFR4 inhibition is a potential mechanism to target metastasis in PDAC patients.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"35 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719690","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":"Advances and obstacles of T cell-based immunotherapy in gynecological malignancies","authors":"Xi Zhao, Jialing Ran, Shenglong Li, Jinxin Chen","doi":"10.1186/s12943-025-02411-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02411-w","url":null,"abstract":" T cell-mediated immunotherapy has revolutionized oncology by enabling precision immune responses against malignant cells. Chimeric Antigen Receptor (CAR) T-cell therapy, which involves genetically reprogramming T lymphocytes to recognize tumor-specific antigens, has shown clinical success in hematologic malignancies and is expanding its potential in solid tumors. Gynecological cancers, including ovarian, cervical, and endometrial carcinomas, present persistent therapeutic challenges due to their aggressive recurrence patterns and limited responses to conventional therapies in advanced disease stages. This review offers a comprehensive analysis of CAR-T cell therapy advancements in gynecologic oncology, examining fundamental biological mechanisms of tumor-immune interactions, clinical progress in target antigen validation, and innovative approaches to counter immunosuppressive tumor microenvironments. Key challenges specific to these malignancies are discussed, such as molecular heterogeneity in endometrial tumors, ascites-mediated T-cell dysfunction in ovarian cancer (OC), and viral antigen dynamics in HPV- driven cervical carcinomas. Recent clinical evidence shows improved therapeutic outcomes through optimized CAR architectures and preconditioning regimens, with objective response rates demonstrating progressive enhancement across successive clinical trial generations. The discussion addresses ongoing limitations regarding treatment durability and manufacturing consistency while exploring emerging solutions such as synthetic biology approaches and multi-omics guided antigen selection. By integrating preclinical insights with translational clinical data, this work establishes a strategic framework for advancing adoptive T-cell therapies in gynecologic oncology, emphasizing the synergistic potential of combining CAR-T technology with personalized neoantigen vaccines and microenvironment-reprogramming agents. These collective advances underscore the transformative prospects of engineered T-cell immunotherapies while providing actionable strategies to overcome the unique biological barriers inherent to female reproductive tract malignancies. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"92 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710676","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":"Hijacking homeostasis: the brain-body neural circuitry in tumor pathogenesis and emerging therapeutic frontiers","authors":"Yong-Fei Wang, Zi-Kai Dong, Wei-Lin Jin","doi":"10.1186/s12943-025-02396-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02396-6","url":null,"abstract":"Cancer research is undergoing a paradigm shift from solely studying tumor cells to investigating systemic effects of cancer in the tumor macroevironment, with an emphasis on the interactions between host organs and tumors. The theory of homeostasis is an important basis for explaining biological functions from the perspective of the organism. Organic homeostasis relies on brain-body crosstalk through interception, immunoception, nociception and other supervisory processes, guaranteeing normal physiological function. Recent studies reveal that malignant tumors can hijack and exploit the brain and its central-peripheral neuronal networks to disrupt the body's homeostasis. Tumors likely disrupt normal brain-body crosstalk by establishing bidirectional brain-tumor connections. On the contrary, organism utilize these mechanisms to hinder tumorigenesis and progression. Standing at the perspective of brain-body crosstalk also promotes the conceptional evolution of cancer initiation and development, and more importantly, provides additional insight for cancer treatment. In this review, we summarize current knowledge about brain-body crosstalk under tumor-bearing contexts and propose some novel anti-cancer strategies. Brain-body crosstalk participates in the battle between tumors and the organism: The homeostasis of the organism is collectively maintained by interoception, nociception, neuroception, endocriception, metaboception and immunoception. However, in tumor states, tumors hijack the brain-body crosstalk system to exploit these homeostatic mechanisms, thereby constructing a macroenvironment conducive to their survival and progression. While tumors hijack the brain-body crosstalk to reestablish homeostasis, the host organism simultaneously counteracts the tumor through brain-body crosstalk, safeguarding its intrinsic homeostasis from disruption. The brain-body crosstalk between tumors and multiple organs mediated by the HPA axis-driven humoral regulation and the sympathetic and parasympathetic nerves plays a significant role in the battle between tumors and the organism. TME, tumor microenvironment; HPA, hypothalamic-pituitary-adrenal; SAS, sympatho-adrenal system. This figure was created using BioRender ( https://biorender.com/ ). ● Cancer research has experienced a conceptional evolution, from simply regarding cancer as an unorganized cell mass to a newborn organ. Therefore, standing at the perspective of interactions between organs provides novel insight for this area. ● The organic homeostasis is supervised and exerted respectively by interception, nociception, neuroception, endocriception, metaboception and immunoception, which are tightly associated with brain and other components of the nervous system. ● Tumors could hijack the brain-body crosstalk to facilitate their own survival and progression. In turn, the host could utilize this axis to constrain cancer development, and ideally promote cancer elimination. ● According to theory of brain-b","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"52 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701494","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":"An immune responsive tumor microenvironment imprints into PBMCs and predicts outcome in advanced pancreatic cancer: lessons from the PREDICT trial","authors":"Anton Lahusen, Manfred P. Lutz, Rui Fang, Martina Kirchner, Sarah Albus, Klaus Kluck, Meinolf Karthaus, Andreas Schwarzer, Gabriele Siegler, Alexander Kleger, Thomas J. Ettrich, Alexander Becher, Sabine Höfling, Jens T. Siveke, Jan Budczies, Andrea Tannapfel, Albrecht Stenzinger, Phyllis Fung-Yi Cheung, Tim Eiseler, Thomas Seufferlein","doi":"10.1186/s12943-025-02406-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02406-7","url":null,"abstract":"Prognosis in advanced pancreatic ductal adenocarcinoma (aPDAC) is particularly poor, only few patients benefit from treatment, and there are few biomarkers. The PREDICT trial examined whether first-line time-to-treatment failure (TTF1) predicts second-line treatment failure (TTF2) in aPDAC patients but found no association. We hypothesized that the tumor immune microenvironment (TiME) could correlate with the outcome in this trial and assessed whether tissue features were reflected in peripheral blood. PREDICT patients received 5-FU/LV plus nanoliposomal irinotecan as second-line treatment. We stratified patients by shortest vs. longest TTF2 and analyzed 20 treatment-naïve tumor tissues samples via transcriptomics and immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) from 82 patients collected prior to second-line therapy underwent flow cytometry and gene expression profiling. A machine learning pipeline integrated PBMC and clinical data to predict second-line outcome including external validation in 30 patients. Long-TTF2 tumors exhibited an immune-active (“hot”) TiME with cytotoxic CXCR3+CD8+-T-cell infiltration. PBMC analysis showed that these immune features were reflected in peripheral blood after one line of treatment. A novel 7-feature PBMC-based model (“TTF2Pred”) accurately predicted TTF2 and overall survival, outperforming clinical or CA19-9 models and was confirmed in an external validation cohort. Long-TTF2 patients exhibited more circulating CXCR3⁺-T-cells and plasmacytoid dendritic cells. Short-TTF2 patients had more platelet-leukocyte aggregates. An immune-active, treatment-naïve TiME predicts a better second-line outcome, and these characteristics imprinted into PBMCs obtained after one line of chemotherapy. We here first describe a minimally invasive, PBMC-based predictor of second-line outcome as a powerful prognostic tool for triaging patients. ClinicalTrials.gov NCT03468335 (registered March 15, 2018).","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"14 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678034","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}