Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Histone lactylation-boosted AURKB facilitates colorectal cancer progression by inhibiting HNRNPM-mediated PSAT1 mRNA degradation.","authors":"Yuyi Li, Jinjin Peng, Di Wu, Qingxin Xie, Yichao Hou, Linjing Li, Xintian Zhang, Yu Liang, Jing Feng, Jiaqing Chen, Wangshuang Chen, Che Xu, Han Yao, Xiangjun Meng","doi":"10.1186/s13046-025-03498-1","DOIUrl":"10.1186/s13046-025-03498-1","url":null,"abstract":"<p><strong>Background: </strong>Aurora kinase B (AURKB), a key regulator of mitosis, is frequently upregulated in various malignancies, including colorectal cancer (CRC), and is associated with poor prognosis. However, the limited clinical efficacy of AURKB inhibitors suggests the existence of previously unrecognized oncogenic mechanisms that merit further investigation.</p><p><strong>Methods: </strong>AURKB was prioritized through bioinformatic analysis, and its elevated expression in CRC was validated via single-cell RNA sequencing (scRNA-seq) and western blot. The transcriptional activation of AURKB was attributed to H3K18 lactylation, as confirmed by chromatin immunoprecipitation (ChIP)-qPCR. RNA sequencing (RNA-seq) and gene set enrichment analysis (GSEA) were conducted to pinpoint the downstream targets of AURKB. The role of the AURKB/phosphoserine aminotransferase 1 (PSAT1) axis in CRC was further studied using both in vitro and in vivo functional experiments. Mass spectrometry, co-immunoprecipitation (Co-IP), proximity ligation assay (PLA), RNA immunoprecipitation (RIP)-qPCR, and mRNA stability assays were employed to investigate the interplay and potential mechanisms involving AURKB, heterogeneous nuclear ribonucleoprotein M (HNRNPM), and PSAT1.</p><p><strong>Results: </strong>AURKB was identified as an oncogene linked to advanced pathological staging and poor clinical outcomes in CRC. Its transcriptional upregulation was driven by H3K18 lactylation at its promoter. PSAT1 was further identified as a key downstream effector in AURKB-mediated CRC progression. Mechanistically, AURKB bound to HNRNPM and interfered with its interaction with PSAT1 mRNA, thereby suppressing HNRNPM-mediated mRNA degradation and ultimately increasing PSAT1 protein levels.</p><p><strong>Conclusion: </strong>Our findings uncover a previously unappreciated, kinase-independent function of AURKB in CRC, redefining its therapeutic relevance beyond kinase inhibition. This highlights the need for broader targeting strategies, including PROTAC-mediated degradation of AURKB and pharmacological inhibition of the AURKB/PSAT1 axis, to fully harness its role in CRC treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"233"},"PeriodicalIF":12.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12337393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144818066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resistance to neoadjuvant chemotherapy in breast cancers: a metabolic perspective.","authors":"Manon Desgres, Melis Poyraz, Buse Sari, François P Duhoux, Cédric van Marcke, Cyril Corbet","doi":"10.1186/s13046-025-03500-w","DOIUrl":"10.1186/s13046-025-03500-w","url":null,"abstract":"<p><p>Neoadjuvant chemotherapy (NAC) is a cornerstone in the treatment of early-stage high-risk breast cancers (BC), particularly in triple-negative, HER2-positive, and selected hormone receptor-positive subtypes. However, its effectiveness is frequently hindered by intrinsic or acquired resistance, resulting in a significant residual cancer burden (RCB) in more than half of patients. Despite extensive genomic profiling, reliable predictive biomarkers for treatment response remain limited, impeding the development of personalized therapeutic strategies. Emerging evidence highlights tumor metabolic reprogramming as a key non-genetic mechanism contributing to NAC resistance. In this review, we critically examine current advances in metabolic imaging and metabolomics as tools to predict NAC response in BC. We also discuss the role of the tumor microenvironment (TME), including hypoxia and acidosis, in shaping metabolic plasticity and fostering treatment resistance. Furthermore, we explore novel therapeutic strategies targeting metabolic pathways, ranging from enzyme inhibition to dietary interventions, and the use of advanced preclinical models. Together, these insights offer a metabolic framework for overcoming NAC resistance and advancing precision oncology in early-stage BC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"234"},"PeriodicalIF":12.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12337530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144823123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting NOTCH1-KEAP1 axis retards chronic liver injury and liver cancer progression via regulating stabilization of NRF2.","authors":"Chunxiao Chang, Meng Wang, Jia Li, Sihao Qi, Xiaojuan Yu, Jun Xu, Shengbin Shi","doi":"10.1186/s13046-025-03488-3","DOIUrl":"10.1186/s13046-025-03488-3","url":null,"abstract":"<p><strong>Background: </strong>Chronic liver injury is a key factor in diseases like hepatocellular carcinoma (HCC), steatohepatitis (NASH), and viral hepatitis type B and C (HBV, HCV). Understanding its molecular mechanisms is crucial for effective treatment. The NOTCH1 signaling pathway, though not fully understood, is implicated in liver injury and may be a potential therapeutic target.</p><p><strong>Methods: </strong>Clinical HCC, HBV, HCV and NASH samples and additional in vitro and in vivo performances were subjected to confirm the role of NOTCH1 and its downstream targets via a series of biochemical assays, molecular analysis approaches and targeted signaling pathway assay, etc. RESULTS: The present study first verified the abnormal elevation of NOTCH1 in hepatocytes from patients with steatohepatitis, HCC, HBV, HCV, and mouse models. Crucially, we discovered that hepatocyte-specific NOTCH1 knockout reduces hepatocellular damage in chronic liver inflammation and HCC mouse models, whereas adeno-associated virus serotype 8 (AAV8)-mediated NOTCH1 overexpression in hepatocytes exacerbates liver injury-related phenotype on-setting. Mechanistically, we showed that NOTCH1 has a new role in controlling ferroptosis and oxidative damage in hepatocytes. It interacts with Kelch-like ECH-associated protein 1 (KEAP1) and is directly recruited through its intracellular domain (NICD1). Additionally, the KEAP1 recruited by NOTCH1 impeded the binding stability of KEAP1-NFE2 like BZIP transcription factor 2 (Nrf2), promote the separation of KEAP1 and Nrf2, thereby reducing the stability of Nrf2 and hindering the ubiquitination-related proteasome degradation of Nrf2. Crucially, we also discovered that NOTCH1's ANK domain is essential for NICD1-KEAP1 contacts and signaling activation. The inability of NOTCH1 with ANK domain mutants (ΔANK) to connect with KEAP1 and increase its expression emphasizes the importance of the ANK domain in KEAP1-NRF2 signaling. By reversing the downregulation of KEAP1 and the overexpression of NRF2, ANK function is linked to ferroptosis and ROS buildup. ANK domain targeting may slow the course of HCC and liver damage.</p><p><strong>Conclusions: </strong>Targeting the NOTCH1-KEAP1-NRF2 axis as a possible chronic hepatic injury therapy is supported by these findings, which identify NOTCH1-KEAP1 as an NRF2 suppressor that accelerates the progression of liver injury.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"232"},"PeriodicalIF":12.8,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCT196969 inhibits TNBC by targeting the HDAC5/RXRA/ASNS axis to down-regulate asparagine synthesis.","authors":"Qiong Yuan, Qi Wang, Jun Li, Liyang Yin, Shu Liu, Xuyu Zu, Yingying Shen","doi":"10.1186/s13046-025-03494-5","DOIUrl":"10.1186/s13046-025-03494-5","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) seriously threatens the health of patients, and new therapeutic targets and drugs need to be explored. Studies have shown that CCT196969 can inhibit melanoma and colorectal cancer. However, the role of CCT196969 in TNBC is unclear.</p><p><strong>Methods: </strong>CCT196969 inhibited TNBC via in vitro and in vivo experiments. Transcriptomic analysis, metabolomics analysis, proteomic analysis, and other experiments were used to determine that CCT196969 inhibited asparagine synthetase (ASNS) expression and downstream mTOR signaling pathway, and that Retinoid X Receptor Alpha (RXRA) was the upstream transcription factor that regulated ASNS. The binding sites of RXRA and ASNS promoter were determined by luciferase and Chromatin Immunoprecipitation (CHIP) assay. Histone Deacetylase 5 (HDAC5) was confirmed as the key target of CCT196969 by target capture assay, Cell thermal shift assay (CETSA), Surface plasmon resonance (SPR) and other experiments. qPCR, CHX tracer, MG132, immunofluorescence (IF) and Co-Immunoprecipitation (CO-IP) assay were used to detect the regulation of HDAC5 on RXRA transcription and post-translation level, and the key domains of interaction and binding between HDAC5 and RXRA. The binding sites of HDAC5 and RXRA were predicted by PyMOL software. The effect of HDAC5 on the acetylation and ubiquitination levels of RXRA was examined by CO-IP experiment. The deacetylation site of HDAC5 to RXRA was investigated by IP experiments and mass spectrometry.</p><p><strong>Results: </strong>This study reveals that CCT196969 can inhibit TNBC by down-regulating the expression of ASNS, inhibiting asparagine synthesis and downstream mTORC pathway. Mechanistically, CCT196969 targeted and inhibited HDAC5, reducing the interaction of its 1-291 region with RXRA's 1-98 region, and further resulting in an increase in RXRA acetylation (K410 and K412) and a decrease in ubiquitination levels. Together, these effects up-regulated the transcriptional and post-translational levels of RXRA. Finally, RXRA inhibited the expression of ASNS at the transcriptional level by binding to the - 1114/-1104 region on the ASNS promoter as a transcription suppressor.</p><p><strong>Conclusions: </strong>This study reveals a previously unrecognized anti-TNBC mechanism of CCT196969 through the HDAC5/RXRA/ASNS axis. This provides potential candidate targets for the treatment of TNBC and a theoretical basis for the clinical treatment of TNBC patients with CCT196969.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"231"},"PeriodicalIF":12.8,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glioblastoma metabolomics: uncovering biomarkers for diagnosis, prognosis and targeted therapy.","authors":"Susan Costantini, Elena Di Gennaro, Giulia Fanelli, Palmina Bagnara, Chiara Argenziano, Carmen Maccanico, Marco G Paggi, Alfredo Budillon, Claudia Abbruzzese","doi":"10.1186/s13046-025-03497-2","DOIUrl":"10.1186/s13046-025-03497-2","url":null,"abstract":"<p><p>Glioblastoma (GBM) is characterized by rapid growth, high molecular heterogeneity, and invasiveness. Specific aggressive factors are represented by MGMT promoter methylation, and IDH mutation status. Current standard-of-care for GBM includes surgical resection, followed by radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide. However, patients almost invariably succumb due to therapy resistance and disease recurrences. Therefore, novel therapies for GBM are urgently needed to improve patient survival, necessitating the identification of new diagnostic and prognostic biomarkers, as well as therapeutic targets.In this context, \"omics\" technologies, such as metabolomics and lipidomics, can generate vast amounts of data useful to elucidate the complex molecular mechanisms driving this disease, and discover potential novel biomarkers and therapeutic targets. Our review aims to highlight the current literature on the metabolomics studies conducted on GBM biological matrices, such as in vitro and in vivo models, tissues and biofluids, including plasma, saliva and cerebrospinal fluid.From the data reported here, it appears that metabolic reprogramming in GBM is characterized by dysregulation in multiple pathways, particularly glycolysis (Warburg effect), amino acid metabolism, and the urea cycle, and the metabolic changes disclose promising tumor targets.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"230"},"PeriodicalIF":12.8,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detecting actionable mutations from matched plasma-based versus tissue next-generation sequencing in advanced non-small cell lung cancer: a retrospective single centre analysis on site.","authors":"Christophe Bontoux, Caroline Lacoux, Jonathan Benzaquen, Jacques Boutros, Guylène Rignol, Elodie Long-Mira, Sandra Lassalle, Maryline Allegra, Doriane Bohly, Mathieu Garcia, Christelle Bonnetaud, Olivier Bordone, Jean-Marc Félix, Virginie Lespinet-Fabre, Virginie Tanga, Charles-Hugo Marquette, Valérie Taly, Aurélia Baurès, Simon Heeke, Marius Ilié, Véronique Hofman, Paul Hofman","doi":"10.1186/s13046-025-03480-x","DOIUrl":"10.1186/s13046-025-03480-x","url":null,"abstract":"<p><strong>Background: </strong>Liquid biopsies (LB) are used increasingly to detect actionable mutations in patients newly diagnosed with advanced non-small cell lung cancer (aNSCLC), though tissue biopsies (TB) still remain the gold standard. The value of systematically combining LB and TB next-generation sequencing (NGS) for genomic profiling in these patients remains controversial.</p><p><strong>Methods: </strong>This single-centre retrospective study included 102 matched TB and LB samples collected from aNSCLC patients at diagnosis. Four circulating free DNA (cfDNA)-based NGS assays (1-4) were compared on site for performance and concordance with TB to detect ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) I/II. Additionally, cfDNA droplet digital PCR methylation (ddPCR-met) testing estimated the tumour fraction to refine the interpretation of wild-type (WT) results.</p><p><strong>Results: </strong>Out of 102 patients, 13% had stage IIIB disease, and 11% presented with brain-only metastases. Adenocarcinoma was the predominant subtype (84%). Ninety LB samples yielded interpretable results across the four assays. Positive percent agreement with TB ranged from 56% (assay 2) to 79% (assay 4), with high concordance, particularly for single-nucleotide variants (SNVs). Hybrid capture-based assays (3 and 4) detected eight and seven gene fusions, respectively, while amplicon-based assays (1 and 2) detected only two each. Assay 3 only identified 12 MET amplifications, five of which were confirmed by fluorescence in situ hybridisation (FISH) but were missed by TB-based NGS. Five out of six negative cfDNA samples with ddPCR-met testing were WT across all assays. The plasma-first approach added incremental value, up to 21% (assay 3). Amplicon-based assays were faster and required less input of DNA for analysis. Patients with stage IIIB or brain-only metastases were significantly more likely to have negative/low levels of cfDNA ddPCR-met.</p><p><strong>Conclusions: </strong>LB-based NGS demonstrated high concordance with TB in newly diagnosed aNSCLC, particularly for detection of SNV. Hybrid capture assays showed superior performance in identifying gene fusions and MET amplifications. The incremental value of a plasma-first strategy was limited in this real-life study. Thus, LB-based NGS on site should be seen as a complementary tool to TB-based NGS or an alternative when tissue samples are unavailable. Additionally, cfDNA methylation analysis enhances diagnostic accuracy in specific cases.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"229"},"PeriodicalIF":12.8,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSRP2 promotes the glioblastoma mesenchymal phenotype via p130Cas-mediated NF-κB and MAPK pathways.","authors":"Jiawei He, Liang Zhang, Hao Xu, Chengtian Gao, Wentao Zhao, Bingchang Zhang, Wanhong Han, Wenpeng Zhao, Guowei Tan, Sifang Chen, Ping Zhong, Zhe Shen, Jian Meng, Ziqian Tang, Hanwen Lu, Xin Gao, Zhangyu Li, Wenhua Li, Jianyao Mao, Bosen Liu, Yun-Wu Zhang, Zhanxiang Wang","doi":"10.1186/s13046-025-03484-7","DOIUrl":"10.1186/s13046-025-03484-7","url":null,"abstract":"<p><strong>Background: </strong>Cysteine-rich protein 2 (CSRP2) plays a role in a variety of biological processes including cell proliferation and differentiation. However, whether and how CSRP2 participates in the malignancy of glioblastoma multiforme (GBM), including its proneural-to-mesenchymal transition (PMT), remains unclear.</p><p><strong>Methods: </strong>CSRP2 expression in low-grade and high-grade gliomas was analyzed, and survival analyses were performed in patients with gliomas with high and low CSRP2 expression in various tumor databases. Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were used to detect the expression of CSRP2 in GBM and control brain tissues. CSRP2 function in GBM was determined by a series of functional tests in vitro and in vivo. WB, co-immunoprecipitation (co-IP) and immunofluorescence were used to determine the relation between CSRP2 and p130Cas. Mechanisms of CSRP2 involvement in GBM progression were analyzed with gene set enrichment analysis and KEGG enrichment analysis in available databases. WB was used to determine the relation between CSRP2 and PMT markers, NF-κB and MAPK signaling-related proteins, and apoptosis-related proteins. Microscale thermophoresis assay was used to analyze whether mitoxantrone (MTO) and CSRP2 could bind. MTO function was determined by a series of functional tests in vitro, while the relation between MTO and PMT markers, NF-κB and MAPK signaling-related proteins, and apoptosis-related proteins was analyzed by WB in GBM cell lines stably overexpressing CSRP2.</p><p><strong>Results: </strong>We found that CSRP2 expression significantly increased in GBM, especially mesenchymal GBM, and that glioma patients with high CSRP2 expression possibly had poor prognosis. CSRP2 overexpression in GBM cells promoted proliferation, colony formation, migration, invasion, temozolomide resistance, and PMT in vitro and tumor formation in vivo. While knockdown of CSRP2 had the opposite effects. Mechanistically, we revealed that CSRP2 interacted with p130Cas, thereby regulating the NF-κB and the MAPK signaling pathways. CSRP2 overexpression and knockdown increased and decreased p130Cas levels and NF-κB and MAPK activities, respectively. Both p130Cas downregulation and NF-κB inhibition reversed the elevated PMT and NF-κB and MAPK activities resulted from CSRP2 overexpression. Finally, we identified that MTO bound CSRP2 and inhibited the malignant effects of CSRP2 overexpression on GBM cells.</p><p><strong>Conclusions: </strong>Our findings demonstrate that CSRP2 promotes GBM malignancy including PMT and temozolomide resistance through activating p130Cas-mediated NF-κB and MAPK signaling pathways. Inhibiting CSRP2 function, including using MTO, may become a novel therapeutic approach for GBM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"228"},"PeriodicalIF":12.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting tumor-associated macrophages to overcome immune checkpoint inhibitor resistance in hepatocellular carcinoma.","authors":"Fen Liu, Xianying Li, Yiming Zhang, Shan Ge, Zhan Shi, Qingbin Liu, Shulong Jiang","doi":"10.1186/s13046-025-03490-9","DOIUrl":"10.1186/s13046-025-03490-9","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains a critical global health concern, particularly in regions with high endemicity of hepatitis B, hepatitis C, and non-alcoholic fatty liver disease. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a promising therapeutic strategy for advanced HCC. Despite encouraging results, primary and acquired resistance to ICIs continues to pose significant challenges in clinical practice. Recent research has identified tumor-associated macrophages (TAMs) as key contributors to immune evasion and ICI resistance in HCC, primarily through polarization to the M2 phenotype. M2-polarized TAMs secrete a range of immunosuppressive cytokines that inhibit T cell activation and promote tumor progression through processes such as angiogenesis and epithelial-mesenchymal transition. These mechanisms compromise the efficacy of ICIs and facilitate tumor expansion and metastasis. This review summarizes the role of TAM-related signaling pathways in driving immune evasion and ICI resistance in HCC, with particular emphasis on the contribution of TAM surface receptors and chemokines in immune suppression. Additionally, the review highlights emerging insights into TAM metabolic reprogramming and transcriptional regulation, which have been closely linked to ICI resistance. Furthermore, we explore promising therapeutic strategies targeting TAMs and their associated signaling pathways to enhance ICI efficacy in HCC. Integrating these novel approaches could potentially overcome TAM-driven immune evasion and ICI resistance, boosting the efficacy of immunotherapy and improving patient prognosis in HCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"227"},"PeriodicalIF":12.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1.","authors":"Adrian Weich, Johannes Berges, Cindy Flamann, Katrin Bitterer, Krishna Pal Singh, David Chambers, Christopher Lischer, Xin Lai, Olaf Wolkenhauer, Carola Berking, Gerhard Krönke, Shailendra Gupta, Heiko Bruns, Julio Vera, Research Group Macrophages","doi":"10.1186/s13046-025-03478-5","DOIUrl":"10.1186/s13046-025-03478-5","url":null,"abstract":"<p><strong>Background: </strong>The metastatic microenvironment is often rich in tumor-associated macrophages (TAMs). In uveal melanoma (UM), high levels of TAMs positively correlate with tumor progression and poorer prognosis. We hypothesize that the immunomodulation of TAMs can remodel the UM tumor microenvironment and make it more susceptible to therapeutic interventions.</p><p><strong>Methods: </strong>In our work, we designed a novel computational pipeline that combines single-cell transcriptomics data, network analysis, multicriteria decision techniques, and pharmacophore-based docking simulations to select molecular targets and matching repurposable drugs for TAM immunomodulation. The method generates a ranking of drug-target interactions, the most promising of which are channeled towards experimental validation.</p><p><strong>Results: </strong>To identify potential immunomodulatory targets, we created a network-based representation of the TAM interactome and extracted a regulatory core conditioned on UM expression data. Further, we selected 13 genes from this core (NLRP3, HMOX1, CASP1, GSTP1, NAMPT, HSP90AA1, B2M, ISG15, LTA4H, PTGS2, CXCL2, PLAUR, ZFP36, TANK) for pharmacophore-based virtual screening of FDA-approved compounds, followed by flexible molecular docking. Based on the ranked docking results, we chose the interaction between caspase-1 and clindamycin for experimental validation. Functional studies on macrophages confirmed that clindamycin inhibits caspase-1 activity and thereby inflammasome activation, leading to a decrease in IL-1β, IL-18, and gasdermin D cleavage products as well as a reduction in pyroptotic cell death. This clindamycin-mediated inhibition of caspase-1 was also observable in TAMs derived from the bone marrow of multiple myeloma patients.</p><p><strong>Conclusions: </strong>Our computational workflow for drug repurposing identified clindamycin as an efficacious inhibitor of caspase-1 that suppresses inflammasome activity and pyroptosis in vitro in TAMs.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"225"},"PeriodicalIF":12.8,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144785842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Inhibition of autophagy enhances the antitumor efficacy of T/CAR T cell against neuroblastoma.","authors":"Francesca De Mitri, Manuela Giansanti, Ombretta Melaiu, Dorothee Haas, Stefan Ebert, Nicola Tumino, Elisabetta Vulpis, Francesca Gatto, Beatrice Martuscelli, Manuela Antonioli, Elisabetta Sangiuliano, Simona Caruso, Marco Scarsella, Cristiano De Stefanis, Veronica Marabitti, Silvia Campello, Doriana Fruci, Paola Vacca, Ignazio Caruana, Francesca Nazio","doi":"10.1186/s13046-025-03492-7","DOIUrl":"10.1186/s13046-025-03492-7","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"226"},"PeriodicalIF":12.8,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144785841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}