Molecular Cancer最新文献

{"title":"Exploring clinically anchored therapeutic stratification and tumor-stroma heterogeneity using patient-derived 3D bioprinted primary liver cancer models.","authors":"Kai Zhang, Liwei Du, Minghao Sun, Yuce Lu, Mingchang Pang, Shangze Jiang, Xiyue Liu, Jiaxun Dong, Bao Jin, Fu Xu, Hang Sun, Jiangang Zhang, Huiyu Yang, Xinting Sang, Shunda Du, Haitao Zhao, Haifeng Xu, Yilei Mao, Huayu Yang","doi":"10.1186/s12943-026-02751-1","DOIUrl":"https://doi.org/10.1186/s12943-026-02751-1","url":null,"abstract":"<p><strong>Background: </strong>The marked heterogeneity of primary liver cancer (PLC), together with the dynamic influence of the tumor microenvironment (TME), remains a major challenge to precision oncology. As currently available therapies provide limited benefit for many patients and robust preclinical platforms for rapid, patient-specific treatment stratification are lacking, there is an urgent need for models that faithfully preserve individual tumor architecture and cellular diversity.</p><p><strong>Methods: </strong>We established three-dimensional bioprinted primary liver cancer (3DP-PLC) models comprising 61 patient-derived monocultures and 34 co-culture models with patient-matched cancer-associated fibroblasts (CAFs). To explore the correlation between ex vivo models and clinical drug response, we developed a clinically anchored hybrid stratification framework for response classification. In parallel, the 3DP-PLC/CAF co-culture biobank was used to investigate stromal regulation of therapeutic response.</p><p><strong>Results: </strong>These 3DP-PLC constructs preserved the histological features, biomarker expression patterns, mutational landscapes, and transcriptomic profiles of their corresponding parental tumors. Drug-sensitivity profiling across the biobank revealed substantial intertumoral heterogeneity in therapeutic responses. The clinically anchored hybrid stratification framework integrating ex vivo pharmaceutical profiles with external clinical benchmark data enabled interpretable response classification and demonstrated clinical relevance in patients receiving neoadjuvant or adjuvant targeted therapy. In parallel, the 3DP-PLC/CAF co-culture biobank, combined with single-cell transcriptomic analysis, recapitulated fibrous ring-like architecture and revealed CAF-associated drug-resistant states.</p><p><strong>Conclusions: </strong>These findings support 3DP-PLC as a high-fidelity and scalable platform for personalized therapeutic stratification and mechanistic investigation of tumor-stroma interactions in PLC.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149270863","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":"Integrative multi-omics of esophageal squamous cell carcinoma reveals immune alterations and lactylation-driven mechanisms in metastatic progression.","authors":"Yanan Pang, Ye Gao, Guobin Liu, Jingxiang Zhao, Han Lin, Yilin Wang, Lei Xin, Wei Wang, Yan Bian, Yunfei Jiao, Qiuxin Li, Zengjun Li, Zhaoshen Li, He Huang, Luowei Wang","doi":"10.1186/s12943-026-02755-x","DOIUrl":"https://doi.org/10.1186/s12943-026-02755-x","url":null,"abstract":"<p><strong>Background: </strong>Esophageal squamous cell carcinoma (ESCC) is highly lethal owing to its early and aggressive metastasis, yet the underlying multi-layer molecular mechanisms remain incompletely understood, limiting therapeutic advances.</p><p><strong>Methods: </strong>We performed integrative multi-omics profiling (including genomics, transcriptomics, proteomics, and lactylome) on 99 matched primary tumor, metastatic lymph nodes, and normal esophagus tissue samples from 36 patients with metastatic ESCC. Molecular changes and cross-omics interactions associated with the metastatic cascades were characterized. Key findings were validated by immunohistochemistry and survival analysis in an independent cohort of 116 ESCC patients. Further functional and mechanistic studies were conducted using in vitro and a tail-vein experimental lung metastasis model.</p><p><strong>Results: </strong>Our analysis revealed pronounced disturbance in immune-related pathways closely associated with metastatic progression and poor prognosis. Intercellular adhesion molecule 1 (ICAM1) was identified as a critical factor of ESCC invasion and metastasis. Additionally, lysine-lactylated proteins were predominantly involved in cytoskeleton, focal adhesion and glycolysis pathways during ESCC metastasis. Integrative analysis revealed that the lactylome interacts with the genome and transcriptome through both cis- and trans-regulatory mechanisms, primarily in immune and metabolic pathways. Notably, lactylation of phosphoglycerate mutase 1 (PGAM1) at residue K251 enhances its interaction with actin gamma 1 and promotes metastatic phenotypes. ICAM1 and PGAM1 K251 lactylation represent two independent metastasis-associated mechanisms identified from the same multi-omics dataset.</p><p><strong>Conclusions: </strong>This integrative multi-omics characterization provides a comprehensive resource for metastatic ESCC research and identifies K251-lactylated PGAM1 as a candidate prognostic biomarker and mechanistic lead warranting further preclinical validation.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149270927","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 profiling defines cellular ecosystems and malignant cell state coupling across pan-cancer tumor microenvironments.","authors":"Xiaoxiao Yang, Yang Tong, Yuting Wang, Peng Xie, Xin Li, Jiapei Yuan, Yang Yang","doi":"10.1186/s12943-026-02741-3","DOIUrl":"10.1186/s12943-026-02741-3","url":null,"abstract":"<p><p>Tumors are embedded within complex microenvironments composed of malignant, immune and stromal cells, yet how coordinated cellular organization shapes tumor biology across cancers remains incompletely understood. Here we integrate single-cell transcriptomic profiles from over two million cells spanning 19 human epithelial cancers to construct a comprehensive pan-cancer atlas of tumor microenvironment (TME) organization. We identify cell subsets selectively enriched in tumors compared with normal tissues and show that their relative abundance is associated with clinical outcomes. By clustering tumors according to their cellular composition, we define eight recurrent cellular ecosystem subtypes that capture coordinated variation in immune and stromal architectures across cancer types. Comparative analyses reveal that these ecosystem states are associated with distinct tumor-intrinsic molecular programs, including differences in signaling pathway activity, transcriptional regulation and copy number alterations. We further uncover subtype-specific patterns of ligand-receptor interactions linking malignant cells with immune and stromal compartments and provide independent spatial support for these interactions using spatial transcriptomic data. Together, this work provides a unified framework for tumor ecosystem stratification and highlights cellular organization as a key dimension of tumor heterogeneity with potential implications for precision cancer therapy.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13688759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149238986","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":"Ribosome biogenesis and selective translational control as oncogenic vulnerabilities in hematologic malignancies.","authors":"Juan Luiz Coelho-Silva, João Agostinho Machado-Neto","doi":"10.1186/s12943-026-02749-9","DOIUrl":"10.1186/s12943-026-02749-9","url":null,"abstract":"<p><p>The translation of the transcriptome into a functional proteome is not a passive readout of mRNA abundance but a primary regulatory layer that actively shapes the oncogenic landscape. In hematologic malignancies, convergent oncogenic signaling pathways, including MYC, PI3K/AKT/mTOR, and tyrosine kinase fusions, directly reprogram the translational apparatus, driving a qualitative shift toward the selective synthesis of pro-survival, proliferative, and stemness-associated proteins. This deregulated program is orchestrated through multiple interconnected axes: the accelerated biogenesis of ribosomes within the nucleolus, the assembly of the eIF4F initiation complex, the activation of stress-adaptive programs like the integrated stress response (ISR), and a sophisticated layer of epitranscriptomic, tRNA, and RNA-binding protein-mediated regulation. Hematologic cancers provide a uniquely informative framework for deconstructing these processes, illustrated by inherited ribosomopathies, such as Diamond-Blackfan anemia syndrome and Shwachman-Diamond syndrome, which resolve the paradox of how ribosomal insufficiency can evolutionarily transition into malignant transformation. Beyond pathogenesis, the translational machinery represents a rich landscape of actionable vulnerabilities. Pharmacological targeting of RNA Polymerase I, eIF4A, and the ISR has demonstrated selective antitumor activity and synergistic potential with established therapies, including BCL-2 inhibition. This review synthesizes mechanistic and clinical evidence to position the ribosome as an active regulatory node rather than a passive decoding machine. We further examine the challenges facing the field, including translational plasticity under therapeutic pressure, the lack of validated companion biomarkers, and the emerging role of translational control in modulating anti-tumor immunity. Ultimately, we argue that defining the disease-specific translational states of leukemia and lymphoma is essential for the next generation of precision oncology, moving beyond genomic landscapes toward a proteomic-centered understanding of malignancy.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228244","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":"Spatial multi-omics analyses of the tumor immune microenvironment: advances and novel therapeutic avenues.","authors":"Haoyu Wang, Yuze Zhu, Maoqian Fang, Xiaoli Zhang, Peng Su, Hongyuan Liang, Dan Dong, Lin Li, Kefeng Wang","doi":"10.1186/s12943-026-02740-4","DOIUrl":"10.1186/s12943-026-02740-4","url":null,"abstract":"<p><p>The tumor immune microenvironment (TIME) is a spatially organized ecosystem in which the distribution and interaction of cellular and molecular components have a significant impact on disease progression and therapeutic response. Traditionally, bulk analyses have failed to capture the critical spatial context governing these dynamics. The latest breakthroughs in spatial multi-omics technologies, including spatial transcriptomics, proteomics and metabolomics, have completely transformed our ability to characterize the TIME at unprecedented resolution. These advanced platforms enable precise mapping of immune cell distribution, reconstruction of intercellular communication networks, and identification of pattern structures such as tertiary lymphoid structures (TLS). We reviewed the current experimental methods of spatial omics and highlights how their applications provide novel insights into tumor biology. We further discussed how insights from spatial profiling could inform the development of novel therapeutic strategies aimed at actively remodeling the TIME, provide information for prognosis prediction, and shape responses to treatments such as immunotherapy. Despite the challenges in standardization and clinical translation, spatial multi-omics provides an indispensable dimension for understanding tumor immunobiology, paving the way for more precise tumor diagnosis, prognosis and treatment methods.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228273","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":"Metabolic plasticity underlies ferroptosis resistance driven by mutant p53 in pancreatic ductal adenocarcinoma.","authors":"Adriana Celesia, Filippo Piccoli, Tian Wang, Yushu Hu, Federica Danzi, Antonino Aparo, Barbara Cisterna, Raffaella Pacchiana, Maria Poles, Maria Teresa Scupoli, Claudio Luchini, Stefano Ugel, Massimo Donadelli, Alessandra Fiore","doi":"10.1186/s12943-026-02746-y","DOIUrl":"10.1186/s12943-026-02746-y","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by late diagnosis, rapid progression, and resistance to conventional therapies. Mutations in the tumor suppressor gene TP53 are prevalent in this cancer and have been associated with gain-of-function activities that promote tumor survival. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, represents a potential therapeutic vulnerability. However, the influence of mutant p53 on ferroptosis susceptibility remains poorly understood.</p><p><strong>Methods: </strong>We employed isogenic pancreatic cancer cell models, including CRISPR-Cas9-mediated TP53 Knockout (TP53-KO) and transient overexpression of common mutant TP53 variants, to examine ferroptosis sensitivity. Cell viability, reactive oxygen species accumulation, lipid peroxidation, mitochondrial integrity, and metabolic profiling were assessed following treatment with ferroptosis inducers. Transcriptional changes were analysed by RNA sequencing, and functional contributions of glycolysis and mitochondrial respiration were evaluated using metabolic flux assays. Pharmacological reactivation of wild-type p53 was tested in combination with ferroptosis inducers in vitro and in orthotopic murine models.</p><p><strong>Results: </strong>Deletion of mutant TP53 sensitized pancreatic cancer cells to ferroptosis, accompanied by increased oxidative stress, lipid peroxidation and mitochondrial dysfunction. Mutant TP53 expression preserved mitochondrial integrity and sustained bioenergetic flexibility under ferroptotic stress. Transcriptomic analyses revealed a multi-layered adaptive program, including upregulation of antioxidant and metabolic genes, and activation of PI3K-AKT signaling, which is associated to a selective glycolytic shift to maintain ATP levels. Functional modulation confirmed that glucose supplementation enhanced, whereas glycolytic inhibition impaired, survival under ferroptotic conditions in mutant TP53-expressing cells, but not in TP53-KO cells. Pharmacological reactivation of wild-type p53 disrupted this adaptive network, abrogating glycolytic reprogramming and significantly increasing ferroptotic cell death both in vitro and in vivo.</p><p><strong>Conclusions: </strong>Mutant p53 orchestrates transcriptional and metabolic plasticity that confers ferroptosis resistance in pancreatic cancer. Reactivating wild-type p53 in combination with ferroptosis induction overcomes this resistance, highlighting a therapeutically actionable vulnerability and supporting the development of combinatorial strategies for this aggressive malignancy.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228417","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":"Patient-derived organoids for precision oncology in colorectal cancer: from tumor modeling to clinical translation.","authors":"Barbara Lupo, Irene Catalano, Livio Trusolino","doi":"10.1186/s12943-026-02747-x","DOIUrl":"10.1186/s12943-026-02747-x","url":null,"abstract":"<p><p>Precision oncology in colorectal cancer (CRC) has been profoundly informed by genomic and transcriptomic profiling, yet molecular stratification remains only partially predictive of therapeutic benefit. This reflects a broader challenge: moving from static molecular information to dynamic, adaptive, and time-resolved predictions of drug response for individual patients along their clinical history. In CRC, this challenge is compounded by extensive inter- and intratumoral heterogeneity, clonal evolution, chromosomal instability, phenotypic plasticity and tumor-microenvironment (TME) interactions, all of which reshape therapeutic vulnerabilities over time.Patient-derived organoids (PDOs) have emerged as a functional platform to address this gap, with CRC providing one of the most fertile contexts for their development and application. By preserving key histopathological, molecular, and phenotypic features of parental tumors while remaining experimentally tractable, expandable, and amenable to pharmacological and genetic perturbation, PDOs add a functional layer to precision oncology in CRC. Living organoid biobanks and ex vivo screening studies have shown that PDOs can capture interpatient heterogeneity, uncover mechanisms of sensitivity and resistance, and, in selected contexts, mirror clinical responses to chemotherapy and targeted agents. The same experimental tractability has made these systems powerful tools for investigating tumor initiation and clonal evolution, while enabling exploration of cellular plasticity through the lens of dynamic cellular hierarchies. In parallel, next-generation CRC organoid systems incorporating stromal and immune components may extend functional testing to TME-dependent processes, including response to immunotherapy.In this review, we discuss the conceptual foundations of organoid technology and its emergence as a functional precision oncology platform in CRC. We examine how CRC organoids have advanced understanding of tumor initiation, evolution, chromosomal instability, and phenotypic plasticity; summarize their applications in drug discovery, therapy-response prediction, and resistance modeling; and highlight the development of next-generation multicellular organoid systems incorporating immune and stromal components. Finally, we address the major technical, biological, and clinical challenges that must be overcome to translate PDO-based approaches into robust and clinically actionable tools for precision medicine.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13681796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224478","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":"Radiotherapy and tertiary lymphoid structures: balancing immune activation and immune damage in cancer immunotherapy.","authors":"Yi Zhang, Hongshuai Li, Siyao Lv, Wenjun Meng, Jiamin Guo, Yating Lu, Lina Peng, Wu Chen, Wen Yang, Xingchen Peng","doi":"10.1186/s12943-026-02735-1","DOIUrl":"10.1186/s12943-026-02735-1","url":null,"abstract":"<p><p>Cancer immunotherapy, exemplified by immune checkpoint blockade (ICB), remains strongly influenced by the pre-existing immune organization of the tumor microenvironment. Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates whose density, maturation state, and spatial localization correlate with clinical prognosis and ICB response across several malignancies. Radiotherapy (RT) can reshape this immune context in opposing directions. By inducing immunogenic cell death, antigen release, cGAS-STING/type I interferon signaling, vascular remodeling, and lymphocyte recruitment, RT can create conditions that support TLS-associated antitumor immunity in selected settings. Conversely, high-dose or large-volume irradiation, poorly timed nodal exposure, and collateral injury to lymphocytes, tumor-draining lymph nodes, stromal scaffolds, and high endothelial venules can disrupt established TLSs or prevent their maturation. This review summarizes current evidence on the bidirectional relationship between RT and TLS biology, differentiating validated mechanisms from indirect evidence and hypothesis-generating translational concepts. We expound on how dose, fractionation, timing, irradiated volume, nodal management and radiation modality may influence antigen presentation, lymphocyte availability, and local immune architecture. Potential strategies such as lymph-node-aware planning, proton or heavy-ion therapy, FLASH RT, vascular normalization, STING or LTβR agonism, and ICB combinations are evaluated as investigational approaches rather than established TLS-directed clinical interventions. Future studies should evaluate whether optimized RT regimens can preserve or promote the functional maturation of TLSs, integrating paired tissue biopsies, spatial transcriptomics, advanced imaging, and circulating biomarkers to definitively correlate TLS remodeling with clinical outcomes.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":" ","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13682009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148550120","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 E3 ubiquitin ligases: Mechanistic breakthroughs and novel clinical translation pathways for tumor radioimmunotherapy.","authors":"Qian Yang, Xinruo Xing, Yichun Wang, Xiangyi Wang, Yutong Han, Jiaxin Ren, Zhenyong Zhang, Jun Tang, Jianzhu Zhao","doi":"10.1186/s12943-026-02739-x","DOIUrl":"10.1186/s12943-026-02739-x","url":null,"abstract":"<p><p>The combination of radiation therapy and immunotherapy has become a cornerstone of modern clinical cancer treatment. However, the inherent radiation resistance of tumors and complex immune evasion mechanisms remain major bottlenecks limiting their long-term effects and sustained efficacy. E3 ubiquitin ligases critically influence tumor sensitivity to radioimmunotherapy by controlling protein stability across DNA repair, immune signaling, and stress-response pathways. This review systematically dissects the multidimensional molecular network through which E3 ubiquitin ligases regulate radiosensitivity and immunoresponsiveness. At the intracellular level, we provide an in-depth analysis of how E3 ubiquitin ligases determine the fate of radiation-induced damage repair by precisely regulating the kinetics of the DNA damage response (DDR), cell cycle checkpoints, and apoptosis thresholds. At the extracellular level, this study focuses on the key roles of E3 ubiquitin ligases in reshaping the immune microenvironment, including the maintenance of spatiotemporal stability of immune checkpoints, the fidelity of antigen processing and presentation, and the epigenetic regulation of microenvironmental dynamic plasticity. Recent studies indicate that E3 ubiquitin ligases link radiation-induced DDR signaling to innate and adaptive immune activation, particularly through the induction of immunogenic cell death (ICD) and the calibration of innate immune sensing pathways like cGAS-STING. Finally, we provide a comprehensive synthesis of cutting-edge translational strategies targeting E3 ubiquitin ligases-ranging from canonical inhibitors to transformative proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs)-offering novel paradigms for overcoming therapeutic resistance and refining personalized radioimmunotherapy.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13556034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920576","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":"Spatial proteomics reveals four-stage molecular evolution in cancer immunotherapy-related gastritis.","authors":"Lei Shi, Zhongqiao Lin, Huishan Zhang, Yuping Lu, Zequn Sun, Bin Lan, Huang Xia, Shuimei Luo, Ling Chen, Zhida Wu, Yuyang Huang, Mengru Quan, Xuefeng Wang, Jing Lin, Yu Chen","doi":"10.1186/s12943-026-02737-z","DOIUrl":"10.1186/s12943-026-02737-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet immune-related adverse events (irAEs) including immunotherapy-related gastritis (IRAEG) pose significant clinical challenges-often necessitating treatment interruption that may compromise antitumor efficacy. IRAEG presents with atypical symptoms, lacks specific biomarkers, and shows histopathological overlap with other forms of gastritis, complicating diagnosis and management. Despite increasing clinical recognition, a systematic understanding of spatial molecular alterations across the full disease course remains limited. Here, we used spatial proteomics to map the molecular landscape of IRAEG during disease progression and to define stage-specific patterns of molecular evolution relevant to cancer immunotherapy management.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We analyzed tissue samples from seven patients, including four non-immunotherapy-related gastritis controls and three cancer patients who developed IRAEG following ICI therapy for solid tumors, sampled longitudinally across four disease stages: baseline (G1), acute severe inflammation (G2), early recovery (G3), and complete recovery (G4). Using laser capture microdissection coupled with data-independent acquisition mass spectrometry, we profiled 177 spatially resolved gastric tissue regions. Multiplex immunohistochemistry and immunofluorescence characterized features of the immune microenvironment, while Gene Ontology, KEGG pathway analysis, Gene Set Variation Analysis, and xCell inference enabled functional, metabolic, and immune profiling. Key immune and NET-related findings were further validated by multiplex immunofluorescence in an independent, expanded cohort of IRAEG and non-immunotherapy-related gastritis samples.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;IRAEG was characterized by widespread HLA molecule activation and enhanced antigen processing, resembling the immune phenotype observed in organ transplant rejection. The acute G2 stage exhibited excessive neutrophil extracellular trap formation, profound metabolic suppression, and collapse of immune homeostasis-features that may inform early intervention strategies to preserve ICI treatment continuity. During early recovery (G3), inflammatory injury transitioned toward repair, marked by activation of fatty acid metabolism and PPAR signaling. Notably, even at complete clinical recovery (G4), more than 1,000 proteins remained differentially expressed, reflecting sustained enhancement of metabolic and immune functions and establishing a distinct molecular \"memory\" state with implications for ICI rechallenge decisions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;These findings define four molecularly distinct stages of IRAEG progression and recovery. The stage-specific signatures identified here serve as candidate biomarkers for diagnosis, disease staging, and therapeutic response assessment, and may guide clinical decisions regarding irAE management,","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":" ","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148550094","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}