AI总结:根据提供的论文列表,整体摘要如下:这些医学论文主要围绕**三阴性乳腺癌(Triple-Negative Breast Cancer, TNBC)**的发病机制、免疫逃逸特性、代谢途径以及潜在治疗策略展开深入研究。具体而言,论文探讨了以下几个关键领域: 1. **病毒 mimicry 诱导的免疫反应**:研究发现某些因素可能通过模拟病毒诱导免疫响应,揭示其在三阴性乳腺癌中的作用机制。 2. **NKG2A 的治疗意义**:作为免疫检查点分子之一,NKG2A 在 MHC-I 异源性表达背景下的抗肿瘤免疫逃逸中扮演重要角色,为开发新型免疫疗法提供了理论支持。 3. **ZNF689 缺失与异质性关系**:分析 ZNF689 基因缺陷对肿瘤内异质性和免疫逃逸的影响,强调其在三阴性乳腺癌进展中的潜在贡献。 4. **代谢通路与治疗靶点**:基于代谢重编程的视角,探索三阴性乳腺癌中特定代谢通路的改变,并提出可能的治疗干预靶点。 5. **铁死亡与免疫组合策略**:研究铁死亡(Ferroptosis)在调控肿瘤异质性及逆转免疫逃逸中的作用,同时提出了创新性的免疫联合治疗方案以改善患者预后。总体来看,这些论文聚焦于三阴性乳腺癌这一难治性亚型,从免疫微环境、基因调控、代谢特征及新兴治疗策略等多维度进行系统性剖析,为未来精准医疗和个性化治疗奠定了重要基础。
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共5篇 平均IF=30.9 (13.7-33.3)更多分析
  • 1区Q1影响因子: 13.7
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    1. PRMT inhibition induces a viral mimicry response in triple-negative breast cancer.
    1. PRMT抑制在三阴性乳腺癌中诱导病毒模拟反应。
    期刊:Nature chemical biology
    日期:2022-05-16
    DOI :10.1038/s41589-022-01024-4
    Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors.
  • 1区Q1影响因子: 33.3
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    2. NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer.
    2. NKG2A 是免疫疗法抗性 MHC - I 异源性三阴性乳腺癌的治疗脆弱性。
    期刊:Cancer discovery
    日期:2024-02-08
    DOI :10.1158/2159-8290.CD-23-0519
    Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials. SIGNIFICANCE:Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti-PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance. This article is featured in Selected Articles from This Issue, p. 201.
  • 1区Q1影响因子: 25.9
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    3. ZNF689 deficiency promotes intratumor heterogeneity and immunotherapy resistance in triple-negative breast cancer.
    3. ZNF689 缺陷会促进三阴性乳腺癌的肿瘤内异质性和免疫治疗耐药性。
    期刊:Cell research
    日期:2024-01-02
    DOI :10.1038/s41422-023-00909-w
    Triple-negative breast cancer (TNBC) is an aggressive disease characterized by remarkable intratumor heterogeneity (ITH), which poses therapeutic challenges. However, the clinical relevance and key determinant of ITH in TNBC are poorly understood. Here, we comprehensively characterized ITH levels using multi-omics data across our center's cohort (n = 260), The Cancer Genome Atlas cohort (n = 134), and four immunotherapy-treated cohorts (n = 109). Our results revealed that high ITH was associated with poor patient survival and immunotherapy resistance. Importantly, we identified zinc finger protein 689 (ZNF689) deficiency as a crucial determinant of ITH formation. Mechanistically, the ZNF689-TRIM28 complex was found to directly bind to the promoter of long interspersed element-1 (LINE-1), inducing H3K9me3-mediated transcriptional silencing. ZNF689 deficiency reactivated LINE-1 retrotransposition to exacerbate genomic instability, which fostered ITH. Single-cell RNA sequencing, spatially resolved transcriptomics and flow cytometry analysis confirmed that ZNF689 deficiency-induced ITH inhibited antigen presentation and T-cell activation, conferring immunotherapy resistance. Pharmacological inhibition of LINE-1 significantly reduced ITH, enhanced antitumor immunity, and eventually sensitized ZNF689-deficient tumors to immunotherapy in vivo. Consistently, ZNF689 expression positively correlated with favorable prognosis and immunotherapy response in clinical samples. Altogether, our study uncovers a previously unrecognized mechanism underlying ZNF689 deficiency-induced ITH and suggests LINE-1 inhibition combined with immunotherapy as a novel treatment strategy for TNBC.
  • 1区Q1影响因子: 30.9
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    4. Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets.
    4. 基于代谢途径的三阴性乳腺癌分型揭示了潜在的治疗靶点。
    期刊:Cell metabolism
    日期:2020-11-11
    DOI :10.1016/j.cmet.2020.10.012
    Triple-negative breast cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: MPS1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, MPS1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of lactate dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles.
  • 1区Q1影响因子: 30.9
    5. Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy.
    5. Ferroptosis异质性三阴性乳腺癌揭示了一个创新的免疫疗法的组合策略。
    期刊:Cell metabolism
    日期:2022-10-17
    DOI :10.1016/j.cmet.2022.09.021
    Treatment of triple-negative breast cancer (TNBC) remains challenging. Deciphering the orchestration of metabolic pathways in regulating ferroptosis will provide new insights into TNBC therapeutic strategies. Here, we integrated the multiomics data of our large TNBC cohort (n = 465) to develop the ferroptosis atlas. We discovered that TNBCs had heterogeneous phenotypes in ferroptosis-related metabolites and metabolic pathways. The luminal androgen receptor (LAR) subtype of TNBC was characterized by the upregulation of oxidized phosphatidylethanolamines and glutathione metabolism (especially GPX4), which allowed the utilization of GPX4 inhibitors to induce ferroptosis. Furthermore, we verified that GPX4 inhibition not only induced tumor ferroptosis but also enhanced antitumor immunity. The combination of GPX4 inhibitors and anti-PD1 possessed greater therapeutic efficacy than monotherapy. Clinically, higher GPX4 expression correlated with lower cytolytic scores and worse prognosis in immunotherapy cohorts. Collectively, this study demonstrated the ferroptosis landscape of TNBC and revealed an innovative immunotherapy combination strategy for refractory LAR tumors.
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