Cellular &Molecular Immunology最新文献

{"title":"Th2 cell-mediated ferroptosis as a driver of sebaceous gland dysfunction in atopic dermatitis.","authors":"Xiaoyu Gu, Yi He, Zhichen Li, Xuan Yang, Xinquan Wang, Minxue Shen, Yi Xiao, Christos C Zouboulis, Hong Liu, Xiang Chen, Juan Su","doi":"10.1038/s41423-026-01477-w","DOIUrl":"https://doi.org/10.1038/s41423-026-01477-w","url":null,"abstract":"<p><p>Atopic dermatitis (AD) is a chronic inflammatory skin disease accompanied by reduced sebum production and skin dryness, yet the functional states of the sebaceous gland (SG, a key tissue for sebum production) in the pathogenesis of AD remain unclear. We fully explored the number, morphology, and function of SG in AD through multiomics, animal intervention experiments, and mechanistic studies. Integrated high-resolution and spot-level spatial transcriptomics, single-cell/bulk RNA sequencing, metabolomics, and histological analysis revealed a marked reduction in SG number in AD, accompanied by morphological atrophy and impaired lipid metabolism, which was closely associated with elevated ferroptosis levels in SG. Topical application of the ferroptosis inhibitor ferrostatin-1 (Fer-1) significantly ameliorated AD-like dermatitis in MC903-treated mice, restoring SG morphology and function, while reducing Th2 cell infiltration and lowering transepidermal water loss (TEWL). Spatial transcriptomic mapping and immunofluorescence localization demonstrated Th2 cells exhibited the strongest spatial proximity to SG in AD lesional skin, indicating the effect of Th2 cells on ferroptosis in SG. Further communication profiling indicated that Th2-derived IL-4 may target GPX4 in SG. In vitro, treatment of SG cells (SZ95) with IL-4 increased ferroptosis levels and decreased GPX4 protein expression. Mechanistically, IL-4 enhanced the binding between TRIM15 and GPX4, which mediated the K48-linked ubiquitination and degradation of GPX4. Consistently, blockade of IL-4 or IL-4Rα using an anti-IL-4 antibody or dupilumab effectively alleviated SG ferroptosis, reduced TEWL, and attenuated the severity of AD-like dermatitis. Our study reveals a mechanistic link between Th2 inflammation and SG ferroptosis via IL-4-TRIM15-GPX4-ubiquitination signaling, thus offering new insights into SG dysfunction and skin barrier impairment in AD. CLINICAL IMPLICATIONS: Reduced sebum production and skin dryness are  notable clinical  manifestations of atopic dermatitis (AD). Our study revealed that ferroptosis of the sebaceous gland (SG) may disrupt sebum production in AD, thus offering new insight into AD therapy by highlighting sebum homeostasis as a potential therapeutic target. Sebaceous gland (SG) ferroptosis,  which contributes to reduced sebum production and skin barrier dysfunction in atopic dermatitis (AD), is driven by Th2 cell-derived IL-4  via TRIM15/GPX4 ubiquitination.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149295153","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":"Macrophage biology and immunoregulation in health and disease.","authors":"Haoxin Zhao, Yi-Ju Chou, Stanley Ching-Cheng Huang","doi":"10.1038/s41423-026-01486-9","DOIUrl":"https://doi.org/10.1038/s41423-026-01486-9","url":null,"abstract":"<p><p>Macrophages are versatile immune cells that maintain tissue homeostasis and shape disease progression through continuous adaptation to the local environment. Recent advances in single-cell, spatial, and multiomics technologies have revealed extensive diversity in tissue-specific macrophage identities and their adaptation to physiological and pathological contexts. Emerging evidence indicates that macrophage behavior emerges from the coordinated integration of ontogenetic imprinting, environmental sensing, metabolic rewiring, and epigenetic remodeling. These interconnected layers collectively determine macrophage responses in inflammatory diseases, neurodegeneration, and cancer, creating both challenges and opportunities for therapeutic intervention. In this review, we provide an overview of recent mechanistic insights into the molecular circuits governing macrophage plasticity and function and discuss how this evolving framework can inform next-generation macrophage-based therapeutic strategies to restore immune homeostasis and improve disease outcomes.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149285540","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":"Designing a tumor landscape-modifying vaccine with a unique TLR2/6 agonist for refractory pancreatic cancer.","authors":"Seongmin Cho, Hyeong Yun Kim, Nayoung Kim, Joohee Park, Seonghoon Kim, Ee Chan Song, Hyun Seo Lee, Uijoo Kim, Hamin Ban, Sunkyo Hwang, Jeongwon Mun, Eunhye Kwon, Yoonju Do, Hyo Eun Kim, Ji Hun Suh, Sang Bum Kim, Ina Yoon, Jiwon Kong, Minju Kang, Do Sik Min, Sunghoon Kim","doi":"10.1038/s41423-026-01480-1","DOIUrl":"https://doi.org/10.1038/s41423-026-01480-1","url":null,"abstract":"<p><p>Failure of cancer vaccines in clinical trials has been linked to poor preclinical translatability, immunosuppressive tumor microenvironments (TMEs), suboptimal antigen delivery to antigen-presenting cells, limited human MHC antigenicity, and insufficiently safe immune adjuvants. Therefore, this study aimed to design an integrated cancer vaccine and evaluate its efficacy in a KPC orthotopic pancreatic cancer model containing the G12D mutation. A novel immune adjuvant, C-VAX, was developed from the natural Toll-like receptor 2/6 agonist UNE-C1 and covalently linked to a KRAS^G12D neoantigen and WNT5a, a tumor-associated antigen upregulated in resistant tumors. This integrated vaccine enhanced CD8⁺ T-cell infiltration and reduced α-SMA expression in the TME. The therapeutic effects were further enhanced following anti-PD-1 checkpoint blockade. These findings suggest that vaccines targeting tumor antigens and resistance-associated TME components may promote an immune-responsive TME in refractory cancers.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149285550","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":"p38α acts as a molecular switch to differentially regulate the Flt3 and CD115 pathways in dendritic cell development.","authors":"Yifan Zhou, Jianfeng Wu, Lihao Gong, Xinyi Zhu, Yuanhao Wang, Tao Wu, Lanqi Luo, Yixue You, Sijie Chen, Yuan Yao, Yuhao Jiao, Peng He, Xinrui Fan, Ning Wu, Hongwei Zhou, Jiahuai Han, Li Wu, Chunxiao Liu","doi":"10.1038/s41423-026-01482-z","DOIUrl":"https://doi.org/10.1038/s41423-026-01482-z","url":null,"abstract":"<p><p>DC development requires balanced signaling from cytokines, such as Fms-like tyrosine kinase 3 ligand (Flt3L) and macrophage colony-stimulating factor (M-CSF), but how these pathways are integrated to control lineage fate is not fully understood. Using a murine genetic model, we identified the kinase p38α as a central node that orchestrates this balance. We demonstrated that p38α, which acts as a critical effector downstream of Flt3L, is indispensable for plasmacytoid DC (pDC) differentiation. Mechanistically, the Flt3L-p38α pathway sustains the expression of the E3 ubiquitin ligase Nedd4, which mediates the degradation of the M-CSF receptor (CD115). Consequently, genetic deletion of p38α disrupts this primary Flt3L signaling cascade, leading to Nedd4 downregulation and triggering compensatory upregulation of surface CD115 expression on hematopoietic progenitors. This paradoxically enhanced their differentiation potential, leading to a numerical compensation of pDCs and increased overall myeloid repopulation; the resulting DCs were functionally impaired and exhibited defective production of type I/III interferons and IL-12. Crucially, this functional collapse abrogated their ability to orchestrate antitumor immunity. As a direct consequence, mice with p38α-deficient hematopoiesis failed to mount effective IFN-γ⁺CD8⁺ T-cell responses and were unable to control tumor growth. Our study reveals a novel p38α-Nedd4 molecular switch that integrates signaling from Flt3L and M-CSF to balance the quantity and functional quality of DCs, highlighting p38α as a key determinant of effective cancer immunosurveillance in a murine system.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263550","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":"Dysregulated thymus-ovary axis promotes virtual memory T cell polarization to aggravate PMOS pathology.","authors":"Yaruo Qiu, Huiyu Xu, Wenyu Tian, Weixuan Wang, Chenlei Xu, Yao Feng, Xuyang Zhao, Wen Gao, Rong Jin, Rong Li, Dan Lu","doi":"10.1038/s41423-026-01481-0","DOIUrl":"https://doi.org/10.1038/s41423-026-01481-0","url":null,"abstract":"<p><p>Polyendocrine metabolic ovarian syndrome (PMOS) is traditionally attributed to dysfunction of the hypothalamic-pituitary-gonadal axis, but the contribution of extra-reproductive organs remains unclear. Here, we identify a thymus-ovary pathway linking androgen excess to ovarian inflammation. Androgen receptor signaling in thymic stromal cells induces early thymic involution and impairs thymic output before overt reproductive pathology emerges. Athymic mice and Rag1^-/- mice with preserved thymic stroma are comparably resistant to PMOS-like pathology, supporting an essential role for thymus-derived T cells in disease development. Antibody-mediated depletion further reveals CD8⁺, but not CD4⁺, T cells are required for disease manifestation. Among CD8⁺ T-cell subsets, virtual memory CD8⁺ T (T_VM) cells preferentially expand in patients and experimental models and accumulate in reproductive tissues. These cells exacerbate disease severity and prolong pathology after androgen withdrawal. Mechanistically, ovarian T_VM cells secrete pro-inflammatory cytokines and CCL5, thereby recruiting myeloid cells to the ovary and amplifying local inflammation. Therapeutically, JAK inhibition restricts T_VM-cell differentiation, redirects CD8⁺ T-cell fate away from a cytotoxic CXCR3^high state and ameliorates PMOS-like pathology. These findings identify T_VM cells as key effectors linking androgen-induced thymic remodeling to ovarian inflammation and persistent pathology.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223388","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":"Glutamate attenuates the ILC2 response and allergic airway inflammation via the kainate receptor GluK2.","authors":"Bo Peng, Siying Sun, Lin Zhu, Shufen Zhong, Xixi Chen, Yaguang Zhang, Huacheng Yan, Yidan Sun, Jiajia Lv, Yuying Huang, Jianye Zhang, Bing Sun, Guochao Shi, Wei Tang","doi":"10.1038/s41423-026-01461-4","DOIUrl":"https://doi.org/10.1038/s41423-026-01461-4","url":null,"abstract":"<p><p>Group 2 innate lymphoid cells (ILC2s) play a critical role in initiating the type 2 immune response, particularly in allergic airway diseases. Although the effects of glutamate on the immune system have been reported previously, its role in modulating the function of ILC2s and lung inflammation remains unclear.In this study, we report that the glutamate levels increased in lung tissue following exposure to allergens. Consequently, glutamate was found to restrain ILC2 responses during lung inflammation in mice. Using Rag1^-/- mice, we demonstrated that the inhibitory effect of glutamate on type 2 inflammation was independent of T and B cells. Further ILC2 adoptive transfer experiments in Rag^-/-Il2rg^-/- mice confirmed that glutamate likely exerted its effects by directly targeting ILC2s. In vitro experiments revealed that glutamate suppressed ILC2 function through ionic kainate receptor signaling. Genetic deletion of the kainate receptor subunit GluK2 enhanced ILC2 responses and exacerbated type 2 lung inflammation. Mechanistically, transcriptome and metabolic analyses revealed that glutamate reduced oxidative metabolism in ILC2s, thereby limiting their activation. Consistently, in vivo administration of BPAM344-a positive allosteric modulator that potentiates GluK2 signaling-effectively suppressed allergen-induced type 2 inflammation. Notably, ILC2-specific GluK2 deletion markedly attenuated the anti-inflammatory effects of BPAM344, indicating that its protective effects depend on ILC2-intrinsic GluK2 signaling.These findings demonstrate a novel role for glutamate in restraining ILC2 function, as it plays a protective role in alleviating airway inflammation. We propose that GluK2 activation may offer a promising therapeutic strategy for treating ILC2-driven allergic asthma.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206532","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":"Programmed cell death in inflammation: interactions and holistic perspective.","authors":"Wangzheqi Zhang, Chenglong Zhu, Chunzhen Li, Lizhou Song, Yan Liao, Haoling Zhang, Bin Yi, Zui Zou","doi":"10.1038/s41423-026-01479-8","DOIUrl":"https://doi.org/10.1038/s41423-026-01479-8","url":null,"abstract":"<p><p>Programmed cell death (PCD) is a major regulatory mechanism that maintains tissue homeostasis and immune balance and strongly influences the initiation, progression and resolution of inflammation. Although apoptosis, pyroptosis, necroptosis and ferroptosis are individual PCD modes that are regulated by different molecular mechanisms, they are not mutually exclusive in inflammatory microenvironments. Instead, these pathways are linked via common signaling mediators and regulatory nodes that enable crosstalk, compensatory activation and context-dependent fine-tuning. It is evident that apoptosis, pyroptosis and necroptosis can be coordinated within defined inflammatory platforms, as exemplified by concepts such as PANoptosis. Pathway-specific modeling is inadequate for inflammatory diseases involving multiple PCD modalities, metabolic and organelle stress, immune-cell interactions and tissue-level changes that molecular models cannot capture. Here, an integrated cell death network (ICDN) paradigm is presented as an organizational schema describing how various types of PCD are coregulated through common regulatory pathways in inflamed tissues. This framework does not identify a new mode of cell death per se but rather integrates pathway compensation following extracellular perturbations, disease-specific inflammatory responses, and susceptibility to therapeutic intervention at common network nodes. This review defines the molecular mechanisms and crosstalk of inflammatory pyroptosis, apoptosis, and necroptosis pathways; links recent advances in death modality applications for specific diseases to the ICDN framework; and highlights important current limitations that require further examination, including the need for stronger evidence of dynamic switching across cell death modalities, spatial architecture during inflammation, and reconfiguration at both the multiprotein complex and network levels, such as inflammasome networks.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179699","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":"CRISPRa screen unveils noncanonical NF-κB to boost the antitumor activity of TCR-based CAR-T cells.","authors":"Hanyang Yu, Yingxin Wu, Yue Liu, Ruxue Wei, Zhixiao Zhou, Li Yu, Xin Lin, Jiasheng Wang","doi":"10.1038/s41423-026-01471-2","DOIUrl":"https://doi.org/10.1038/s41423-026-01471-2","url":null,"abstract":"<p><p>Engineering autologous T cells for adoptive therapies has revolutionized cancer treatment, yet limited persistence remains a major barrier to robust clinical responses and durable disease control. Although costimulation with 4-1BB markedly improves CAR-T-cell persistence, no comparably effective approach has been identified to enhance persistence in T-cell therapies that rely on native TCR signaling, including conventional TCR-T cells and synthetic T-cell receptor and antigen receptor (STAR) T cells. To identify intrinsic persistence regulators in a TCR-based context, we performed an in vivo CRISPR activation screen in STAR-T cells and identified the noncanonical NF-κB axis, with RELB as the top hit. Direct RELB overexpression, however, exhibited dose-dependent cytotoxicity, motivating a translational alternative: overexpression of p52, the ncNF-κB transcription partner of RELB. Under prolonged antigen exposure, p52 overexpression sustained proliferation, preserved effector functions, and increased the intratumoral trafficking potential, particularly in CD8⁺ T cells, thereby yielding superior tumor control. Mechanistically, transcriptomic profiling revealed coordinated upregulation of cell cycle programs and chemokine receptors, along with downregulation of apoptosis and exhaustion-associated modules. Moreover, p52 overexpression restored RELB nuclear translocation in the context of PD-1/PD-L1 engagement, indicating partial resistance to checkpoint-mediated suppression and sustained ncNF-κB activity in PD-L1^hi immunosuppressive environments. Collectively, our findings identify p52 as an antigen-dependent enhancer of ncNF-κB, conferring durable persistence and checkpoint resilience on TCR-based T cells and providing a feasible strategy to improve therapeutic effects in solid tumors.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179672","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 H3K27me3-NR1D1-IFN-γ axis in trained macrophages induced by early respiratory virus infection drives non-T2 asthma in children.","authors":"Hanglin Li, Boyang Zheng, Beibei Qin, Wenjian Li, Jia Gao, Mengmeng Li, Wenna Ji, Junhai Wang, Caixia Li, Ling Zhang, Jiaqi Liang, Yiming Zhang, Lijie Zhao, Meiqian Wang, Xiaoqing Zheng, Yuqing Deng, Ruihong Zeng","doi":"10.1038/s41423-026-01470-3","DOIUrl":"https://doi.org/10.1038/s41423-026-01470-3","url":null,"abstract":"<p><p>Unlike that of T2 asthma, the pathophysiology of non-T2 asthma remains largely unexplored. However, increasing evidence supports a role for trained macrophages in asthma. In this study, we utilized a non-T2 asthma mouse model associated with early respiratory viral infection to identify the H3K27me3-NR1D1-IFN-γ axis in lung-trained macrophages, which drives non-T2 asthma by promoting Th1 differentiation. Early infection combined with allergen sensitization induced the formation of trained macrophages, which displayed hyperactive methionine cycling and elevated levels of S-adenosylmethionine (SAM). As a substrate for methyltransferase, SAM enhanced the trimethylation of H3K27, subsequently suppressing the expression of the nuclear receptor subfamily 1 group D member 1 (NR1D1) gene through enrichment at its promoter. Interestingly, NR1D1 interacted with the Ifng gene and negatively regulated its expression. High levels of IFN-γ from trained macrophages were observed because NR1D1 was inhibited by elevated H3K27me3 levels. Following allergen challenge, the increased expression of IFN-γ, MHC-II, and CD80/CD86 in trained macrophages positively regulated the activation and differentiation of Th1 cells, which subsequently produced more IFN-γ, thereby promoting non-T2 asthma. Consistently, in patients with asthma, peripheral blood mononuclear cells (PBMCs) and monocytes downregulated NR1D1 expression, resulting in elevated IFN-γ levels. Conversely, treatment of patient monocytes with an NR1D1 agonist led to a marked decrease in IFN-γ production. In mice, non-T2 asthma was significantly inhibited by either the inhibition of H3K27me3, the activation of NR1D1, or the neutralization of IFN-γ. Our results demonstrate that the H3K27me3-NR1D1-IFN-γ axis in lung-trained macrophages, which is associated with early infection, drives non-T2 asthma during childhood in mice. Consequently, SAM, NR1D1, and IFN-γ may serve as potential drug targets for the treatment of non-T2 asthma.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147124","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":"IGF2BP2 remodels the lung metastatic immune microenvironment to promote bladder cancer metastasis.","authors":"Ming Bai, Tianyao Liu, Hao Wu, Xin Yang, Yue Yin, Ying Sun, Jiazheng Li, Zihan Zhou, Yuanchun Ma, Zihan Zhao, Xiangyu Wu, Liming Wu, Yi Chen, Siyang Liu, Xiang Du, Zihan Hao, Xiangyu Wang, Zhenlin Li, Hongqian Guo, Feng Fang, Ke Zen, Rong Yang","doi":"10.1038/s41423-026-01474-z","DOIUrl":"https://doi.org/10.1038/s41423-026-01474-z","url":null,"abstract":"<p><p>Bladder cancer lung metastasis poses a major therapeutic challenge because of pronounced tumor heterogeneity. However, the mechanisms regulating bladder cancer metastasis remain elusive. Here, we established a lung-tropic bladder cancer subline through iterative in vivo selection, enabling stepwise enrichment of metastatic competence while minimizing intratumoral variability. Using integrated multiomics analyses combined with functional validation, we identified an IGF2BP2-m⁶A-complement axis that is progressively engaged during metastatic evolution and contributes to lung colonization by bladder cancer cells. IGF2BP2 expression increased stepwise during the metastatic cascade and selectively enhanced the translation of m⁶A-modified complement C3 mRNA through direct binding to its 3' region, without altering transcript abundance. Tumor-derived C3 is subsequently processed, thereby promoting neutrophil recruitment and phenotypic remodeling toward a prometastatic, T3-like state. Single-cell transcriptomic profiling revealed that loss of IGF2BP2 disrupted neutrophil recruitment and was accompanied by enhanced T-cell proliferative activity within lung metastatic lesions. Genetic ablation or pharmacological inhibition of IGF2BP2 attenuated neutrophil accumulation and significantly restricted metastatic outgrowth in vivo. Consistent with these experimental findings, elevated IGF2BP2 expression in clinical bladder cancer specimens correlated with advanced disease stage, increased metastatic risk, and poor patient survival. Collectively, our findings reveal a translationally regulated complement-immune circuit that shapes the lung metastatic microenvironment and identify IGF2BP2 as a potential therapeutic target in metastatic bladder cancer.</p>","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134785","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}