Cancer research最新文献

{"title":"A syngeneic murine glioma model recapitulates key molecular, immunologic, and functional features of human glioblastoma to enable therapeutic development","authors":"Katie B. Grausam, Marissa S. Pioso, Julio C. Sanchez, Marissa Li, David Rincon Fernandez Pacheco, Emily A. Hatanaka, Gilbert Herrera, Thomas J. Lai, Eddie Lu, Paul W. Linesch, Naomi Kobritz, Trinh L. Phan, Sophie Ashley, Ariel A. Andrade, Lauren Markus, Jingwen Yao, Xuemo Fan, Bohyeon Yu, Aaron A. Diaz, Linda M. Liau, Moise Danielpour, David A. Nathanson, Robert M. Prins, Joshua J. Breunig, Stephen L. Shiao","doi":"10.1158/0008-5472.can-25-5766","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-5766","url":null,"abstract":"Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults, characterized by diffuse infiltrative lesions, distinct oncogenic alterations, and a suppressive tumor immune microenvironment (TIME). These traits, however, are not fully recapitulated in current syngeneic murine glioma models, thereby limiting the pre-clinical development of novel therapies. Here we developed murine GBM models with patient-specific mutations that shared striking resemblance with human disease. Mosaic analysis with dual-recombinase mediated cassette exchange (MADR) and CRISPR-Cas9 were leveraged to generate autochthonous tumor models with single-copy somatic transgenesis of murine epidermal growth factor receptor variant III (mEGFRvIII) and loss-of-function mutations commonly observed in GBM. Characterization of a model lacking Pten and Cdkn2a (mEGFRvIII-PC) via histopathologic analyses, functional assays, and single-cell RNA sequencing showed these tumors developed as diffuse, infiltrative lesions with ill-defined margins and a necrotic core. The TIME was primarily comprised of microglia with minimal lymphocyte infiltration, recapitulating patient tumors. Furthermore, these tumors displayed intrinsic resistance to immune checkpoint blockade, potentially due to poor myeloid cell antigen presentation and T cell priming. Additionally, mEGFRvIII-PC cells were the most resistant to antigen-specific T cell-induced cytotoxicity and simultaneously promoted T cell exhaustion, while murine interferon-γ (mIFN-γ) stimulation induced a greater response in vitro with enhanced upregulation of PD-L1 relative to MHC-I. In sum, these findings demonstrate the improved fidelity of the mEGFRvIII-PC model to patient tumors and support its use in developing and refining novel therapeutic paradigms for GBM.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"9 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152550","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":"KAT5 is Dual-Function Therapeutic Target with Direct Antitumor and Immunomodulatory Activity in Endometrial Cancer","authors":"Jingyao Lian, Wenshu Li, Ge Zhao, Shiying Li, Tianqi Li, Lijun Huang, Huarong Wang, Zhenhua Hu, Shilei Bi, Zhaowei Tu, Wei Sun, Shuang Zhang","doi":"10.1158/0008-5472.can-26-0507","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-0507","url":null,"abstract":"Epigenetic dysregulation plays a vital role in the progression of endometrial cancer (EC), yet targeted treatment options remain limited. Here, we identified the histone acetyltransferase KAT5 as a therapeutic target in EC. KAT5 was significantly overexpressed in EC and correlated with poor patient outcome. Silencing KAT5 inhibited EC cell proliferation and tumor growth. KAT5-deficient EC cells exhibited impaired cytoskeletal dynamics, leading to heightened DNA damage and increased micronuclei formation. The release of micronuclear DNA into the cytoplasm activated the cGAS-STING pathway, thereby amplifying proinflammatory immune responses. Mechanistically, KAT5 acetylated H2A.Z to transcriptionally activate Arp2/3 complex genes, promoting actin polymerization and chromosomal stability. Inhibition of Arp2/3 or depletion of its subunit ARPC5 replicated the effects of KAT5 loss, whereas restoring ARPC5 mitigated chromosomal instability and cGAS activation. In transplantation models of EC cell lines and syngeneic murine Trp53-/-;Pten-/- EC organoids, pharmacological inhibition of KAT5 with NU9056 suppressed tumor progression and enhanced immune cell infiltration. NU9056 also induced Arp2/3 disruption, genomic instability, and cGAS-STING activation in patient-derived organoids from clinical endometrial cancer samples. Together, these findings highlight KAT5 as a promising therapeutic target in EC that influences chromatin remodeling, cytoskeletal dynamics, and immune modulation.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"26 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172480","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":"INSR Armoring Protects CAR-NK and CAR-T Cells Against Tumor Stroma-Induced CAR Shedding by Maintaining Cholesterol Homeostasis","authors":"Lizhong Yao, Baolong Li, Luke Zhang, Xueliang Zhou, Junyi Hou, Xiongyan Wu, Sheng Lu, Yifan Lu, Ruoyun Zhou, Zhenjia Yu, Zhijian Jin, Huan Zhang, Beiqin Yu, Zhenggang Zhu, Bingya Liu, Jing Sun, Jinping Zhang, Xiaofeng Xue, Jerrold R. Turner, Chao Yan, Liping Su","doi":"10.1158/0008-5472.can-26-1047","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-1047","url":null,"abstract":"While chimeric antigen receptor (CAR)-engineered T and NK cell therapies have revolutionized hematological malignancy treatment, translating this success to solid tumors remains a persistent challenge. Here, we demonstrated a stromal-associated metabolic mechanism in which cancer-associated fibroblasts (CAFs) and macrophage-associated populations in gastrointestinal cancers contribute to CAR loss through CYP27A1-derived 27-hydroxycholesterol (27HC). 27HC triggered membrane cholesterol depletion, destabilizing lipid rafts and promoting the release of full-length CAR in ARF6+CD81+ microvesicle-enriched fractions. NK92 cells chronically exposed to sublethal 27HC adapted to this stress via an AKT-FOXO1-insulin receptor (INSR) signaling cascade that restores cholesterol biosynthesis. Capitalizing on this mechanism, \"metabolically armored\" INSR-overexpressing CAR-NK92 and primary CAR-T cells were engineered, which stabilized lipid rafts, preserved CAR expression, and improved antitumor activity in patient-derived organoids, precision-cut tumor slices, and xenografts. Collectively, these findings identify a stromal-mediated metabolic immune evasion pathway in gastrointestinal tumors, uncovering a potential strategy to potentiate CAR-engineered therapies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"167 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130470","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":"Paired Single-Cell Profiling Reveals Glutathione-Dependent Immune Evasion in Breast Cancer Liver Metastasis","authors":"Cheng Lyu, Meiqi Wang, Haitao Wang, Yixin Qi, Bizhu Chu, Xiaohui Ji, Cuizhi Geng, Zepeng Hou, Lan Jin, Shengnan Guo, Tianhao Li, Dapeng Hao, Zhenchuan Song","doi":"10.1158/0008-5472.can-26-1201","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-1201","url":null,"abstract":"Breast cancer liver metastasis (BCLM) represents a major clinical challenge. Characterizing the differences between primary and metastatic tumors could help identify therapeutic targets for preventing and treating metastasis. Through single-cell transcriptomic sequencing of matched primary tumors and BCLMs from 13 treatment-naïve patients, we uncovered a fundamental paradox in metastatic progression: BCLMs exhibited a highly immune-infiltrated microenvironment characterized by cytotoxic T cell expansion, inflammatory macrophage polarization, and depletion of regulatory T cells, yet they successfully evaded immune-mediated destruction. Metastatic cells retained extensive clonal and genomic diversity from their primary tumors, suggesting a polyclonal metastatic process rather than a stringent metastatic “bottleneck”. Instead, cancer cells featured a metabolic adaptation mechanism in which elevated glutathione (GSH) metabolism in the liver fosters glutamine addiction, creating liver metastasis susceptibility. Integrative regulatory network analyses pinpointed NRF2 as a key regulator associated with GSH metabolism, and functional experiments demonstrated that GSH promoted tumor stemness and attenuated CD8⁺ T cell-mediated antitumor immunity in an NRF2-dependent manner. Inhibition of NRF2 and GSH reduced liver metastasis in vivo and was associated with enhanced antitumor immune responses. Together, this study provides comprehensive single-cell characterization of the immune-metabolic landscape in treatment-naïve BCLM and reveals a potential model in which metastatic success in immune-competent tissues depends on tumor cell-intrinsic metabolic adaptation. These findings provide insights into breast cancer liver metastatic progression and suggest NRF2 and GSH inhibition as a promising therapeutic strategy that could restore immune surveillance in liver metastases.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"15 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The HDAC8–U2AF1 Axis Dysregulates DNA Damage-Responsive RNA Splicing and Creates Targetable Vulnerabilities in Acute Myeloid Leukemia","authors":"Lianjun Zhang, Yu-Hsuan Fu, Wei-Kai Hua, Ying-Chieh Chen, Le Xuan Truong Nguyen, Xin He, Wancheng Guo, Yinghui Zhu, Chi-Yang Tseng, Zhenhua Chen, Haojie Dong, Lei Zhang, Bin Zhang, Jeremy M. Stark, Ling Li, Guido Marcucci, Ya-Huei Kuo","doi":"10.1158/0008-5472.can-25-5027","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-5027","url":null,"abstract":"Despite recent treatment advances using targeted therapies, acute myeloid leukemia (AML) remains a highly lethal disease. Mechanism-based biomarker-informed therapies could expand therapeutic options and enable rational combination strategies. Here, we demonstrated that HDAC8 impairs DNA repair and confers therapeutic vulnerabilities in AML. Analysis of AML patient datasets revealed that HDAC8 is overexpressed in more than half of cases and is associated with dysregulated DNA damage response (DDR) gene expression. Elevated HDAC8 expression induced DNA damage phenotypes and compromised homologous recombination (HR)-mediated repair. Mechanistically, HDAC8 regulated acetylation of the splicing factor U2AF1, which blocked DNA repair by regulating RNA splicing. In response to DNA damage, the acetyltransferase TIP60 acetylated U2AF1 at lysines 23 and 175, modifications required for the interaction of U2AF1 with BRCA1 and BCLAF1 within a DDR–associated spliceosomal complex. HDAC8 promoted the removal of these acetyl groups, disrupting U2AF1–BRCA1–BCLAF1 complex formation and altering DDR-associated RNA splicing. Consequently, HDAC8 hyperactivity drove widespread RNA splicing dysregulation, defective HR repair, and increased sensitivity to both splicing modulators and PARP inhibitors. In preclinical models, including patient-derived xenografts, the splicing modulator H3B-8800 and the PARP inhibitor talazoparib reduced leukemia burden and leukemia stem cell activity, with enhanced efficacy observed in combination. In inv(16)(p13q22) AML, the CBFβ::SMMHC fusion protein exploited the HDAC8–U2AF1 axis to promote genomic instability. These findings identify the HDAC8–U2AF1 axis as a mechanistic driver of DDR dysfunction and genomic instability and uncover actionable, biomarker-informed therapeutic vulnerabilities in HDAC8-high AML.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"9 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149123824","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":"ANXA1 Promotes Endoplasmic Reticulum–Mitochondria Calcium Coupling to Sustain Lenvatinib Resistance in Hepatocellular Carcinoma","authors":"Zeyi Guo, Zhongzhe Li, Tiancheng Lei, Yaguang Ren, Yiran Xu, Meixian Jin, Kunjiang Tan, Jiantao Liu, Chenshuang Zhang, Yizhe Dai, Silue Zeng, Lixue Zhang, Xuyu Fu, Shaohua Li, Chengbo Liu, Feng Shen, Shunjun Fu","doi":"10.1158/0008-5472.can-26-2074","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-2074","url":null,"abstract":"Lenvatinib is the most widely used first-line treatment for advanced hepatocellular carcinoma (HCC). Nevertheless, drug resistance remains a major clinical challenge, highlighting the need to identify the underlying mechanistic drivers. Here, we identified a role for annexin A1 (ANXA1) in promoting lenvatinib resistance by supporting endoplasmic reticulum (ER)–mitochondria communication. Live-cell structured illumination microscopy revealed that ANXA1 deficiency induced the dissociation of ER–mitochondria contact sites (ERMCS), and Ca2+ kinetic analysis revealed that ANXA1 enhanced mitochondrial Ca2+ coupling. ANXA1 promoted ERMCS by directly binding the ER–mitochondria Ca2+ transfer tethers GRP75 and ITPR1 and promoting their interaction. Functionally, ANXA1 sustained oxidative phosphorylation following lenvatinib treatment and promoted cell survival. We further found that ANXA1 RNA stability was governed by an 8-oxoguanine modification–mediated ROS feedback loop. Therapeutically, photoacoustic imaging–guided in vivo analyses demonstrated that targeting this epigenetic–organelle communication feedback loop resensitized HCC to lenvatinib treatment, inhibiting peritumoral angiogenesis and improving the intratumoral hypoxic microenvironment. These findings uncover ERMCS formation as a driver of lenvatinib resistance in HCC, establishing a potential therapeutic strategy for targeting organelle communication to reverse drug resistance.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"8 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130472","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":"Sodium-Glucose Cotransporter SGLT2 Supports Metabolic Fitness and Ferroptosis Resistance in CAR-T Cells to Enhance Activity Against Solid Tumors","authors":"Yaoxin Gao, Xinbin Yang, Xiaowen Mao, Luoming Zhang, Pengju Lv, Baodong Ma, Fuli Qin, Ranran Jin, Lin Wang, Songge Liu, Jianping Ye, Shoukui Hu, Dandan Guo, Xu Wu, Xiwen Ma, Juntang Lin, Zhengyuan Xia","doi":"10.1158/0008-5472.can-26-1157","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-1157","url":null,"abstract":"Antitumor T-cell function is tightly coupled with cellular metabolism, which is severely compromised by glucose deprivation and elevated sodium chloride (NaCl) in the solid tumor microenvironment (TME). Here, we demonstrated that glucose restriction markedly impaired activation, cytotoxicity, and persistence of CAR-T cells while promoting exhaustion, whereas high NaCl partially reversed these defects. Overexpression of the sodium–glucose cotransporter SGLT2 in CAR-T cells to simultaneously enhance glucose and NaCl uptake led to stronger antitumor activity in multiple solid tumor xenograft models. Mechanistically, SGLT2 overexpression elevated glycolysis and mitochondrial fitness, inhibited ferroptosis, and activated the AKT-mTOR pathway. These findings establish a metabolic engineering strategy that boosts glucose utilization in CAR-T cells to overcome TME stress and enhance solid tumor control.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"187 2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130471","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":"Single-Cell and Spatial Transcriptomics Reveal CHCHD3 as a Therapeutic Target to Activate cGAS-STING and Overcome Immunosuppression in Lung Adenocarcinoma","authors":"Mengzhe Zhang,Zekun Li,Zengtuan Xiao,Shuai Jiang,Yiying Di,Taiyang Zhang,Zuo Liu,Meng Yan,Pengpeng Zhang,Yongjie Xie,Zhenfa Zhang","doi":"10.1158/0008-5472.can-25-2727","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2727","url":null,"abstract":"Abstract A substantial proportion of treatment-naive lung adenocarcinoma (LUAD) patients exhibit intrinsic resistance to neoadjuvant chemoimmunotherapy, highlighting the need for mechanism-driven therapeutic strategies. Here, we performed integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics on clinical specimens from the CheckMate 816 trial to define the tumor immune microenvironment (TIME) dynamics associated with therapy resistance. The scRNA-seq data revealed distinct TIME features in non-responders to neoadjuvant chemoimmunotherapy, characterized by the upregulation of CHCHD3. Mechanistically, CHCHD3 acted as a negative regulator of innate immunity by sequestering cGAS in mitochondria. This interaction between the CHCHD3 domain and the cGAS catalytic core reduced the cytosolic cGAS pool, thereby blunting STING-dependent signaling. Consequently, CHCHD3 knockout restored CXCL5/CXCL1 production, reduced M2-like tumor-associated macrophages, and promoted CD8+ T cell infiltration. Integrated virtual and functional drug screening identified TN4510 as a small molecule that disrupts the CHCHD3-cGAS interface. TN4510 treatment effectively restored STING signaling and synergized with chemoimmunotherapy to suppress tumor growth in preclinical models. Together, these findings reveal that CHCHD3 drives chemoimmunotherapy resistance by sequestering cGAS to limit STING activation. Targeting CHCHD3 with TN4510 restores antitumor immunity, offering a translatable strategy to overcome treatment resistance in LUAD.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"16 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088294","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":"Modeling Wilms Tumor Development with Multiple Lineage Human Fetal Kidney Organoids Reveals the Cellular Origin and Specific Drivers of Tumorigenesis","authors":"Xiaofeng Gong,Qing Li,Zhaoting Xu,Jianchen Peng,Yanming Xu,Quanhui Dai,Songnian Yue,Yangyang Ma,Bing Zhao","doi":"10.1158/0008-5472.can-26-0060","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-0060","url":null,"abstract":"Abstract Dysregulation of kidney organogenesis can lead to the development of Wilms tumor (WT), a common pediatric kidney cancer. Although numerous mutations implicated in WT have been identified through genomic studies, the cellular origin and driver mutations in WT remain unclear due to the lack of human models that preserve the complete lineage diversity of the developing kidney. Here, we established an in vitro condition to generate 3D human fetal kidney organoids (FekOs) phenocopying aspects of in vivo renal cellular heterogeneity and complex organization. FekOs faithfully recapitulated the spatial arrangement of ureteric bud (UB) structures and nephron segments. FekOs could be expanded over long time periods. Screening of clinically relevant mutations in WT identified key driver mutations and combinations that result in tumor-like neoplasms. Notably, distinct lineages were isolated from fetal kidney tissues to generate UB organoids and nephron organoids, mapping driver mutations to their specific cellular origins. Together, this model provides insights into how different mutations and their combinations drive Wilms tumorigenesis, providing a scalable platform for advancing human kidney developmental disease research.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"8 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088296","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":"Epigenetic Priming Sensitizes Metastatic Breast Cancer to Checkpoint Blockade by Rewiring the Tumor-Immune Microenvironment","authors":"Yaiza Senent,Robert T. Manguso","doi":"10.1158/0008-5472.can-26-3968","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-3968","url":null,"abstract":"Immune checkpoint blockade (ICB) has shown limited efficacy in metastatic breast cancer. Resistance mechanisms involve suppressive myeloid and stromal populations in the tumor microenvironment (TME). In this issue of Cancer Research, Gonzalez and colleagues integrate single-cell transcriptomics, spatial proteomics, functional immunology, and mathematical modeling to dissect how combined treatment with the histone deacetylase (HDAC) inhibitor entinostat and anti–PD-1/anti–CTLA-4 blockade (EPC) sensitizes these refractory tumors. Work using metastatic mouse models shows that the antitumor response is multifactorial, comprising downregulation of myeloid-mediated CD8+ T-cell suppression (via ICAM-1 and IFNγ signaling) along with increased B-cell and plasma cell activation, antibody production, and tertiary lymphoid structure (TLS) maturation. Some of these findings are further validated in biospecimens from patients on a phase Ib trial treated with the EPC combination treatment. Mathematical modeling formalizes this insight, demonstrating that simultaneous modulation of T-cell activation and myeloid suppression, rather than either alone, is required to drive tumor eradication in silico. This work highlights the increasingly accepted idea that the answer to how current treatments modify and shape tumors is multifactorial. Thus, diversified strategies that include comprehensive analysis of the TME, mathematical modeling tools, and validation in human specimens are required to optimize treatment efficacy. See related article by Gonzalez et al., p. XX .","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":"OF1-OF2"},"PeriodicalIF":11.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088295","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}