当前共找到 2 篇文献分享。
1.
翁凯
(2025-04-05 09:05):
#paper 【doi】10.1038/s41586-025-08732-6；【发表年份】2025年；【期刊】Nature；【标题】VDAC2 loss elicits tumour destruction and inflammation for cancer therapy。本研究发现，电压依赖性阴离子通道2（VDAC2）在肿瘤免疫逃逸中起关键作用。研究者利用CRISPR–Cas9基因筛选技术，发现VDAC2是免疫信号依赖的检查点，限制了干扰素-γ（IFNγ）介导的肿瘤破坏和肿瘤微环境的炎症重编程。研究中，靶向肿瘤细胞中的VDAC2能够增强IFNγ诱导的细胞死亡和cGAS–STING信号通路的激活，显著改善抗肿瘤效果和免疫治疗反应。通过全基因组遗传互作筛选，研究者确定BAK是VDAC2缺失诱导效应的介质。机制上，IFNγ刺激增加了BIM、BID和BAK的表达，而VDAC2的缺失则导致IFNγ诱导的BAK激活失控，进而引发线粒体损伤。随后，线粒体DNA异常释放到细胞质中，触发了cGAS–STING信号通路和I型干扰素反应的强烈激活。重要的是，共同缺失STING信号通路组分会削弱肿瘤细胞中VDAC2耗竭的治疗效果，这表明靶向VDAC2整合了CD8+ T细胞和IFNγ介导的适应性免疫与肿瘤内源性类固有免疫反应。研究结果揭示了VDAC2作为一个双重作用靶点，能够克服肿瘤免疫逃逸，并强调了协同破坏和炎症化肿瘤以实现有效癌症免疫治疗的重要性。
2.
翁凯
(2025-04-03 20:39):
#paper 【doi】10.1016/j.cell.2025.03.018；【发表年份】2025年；【期刊】Cell；【标题】A single-cell atlas reveals immune heterogeneity in anti-PD-1-treated non-small cell lung cancer。本研究的目标是探究非小细胞肺癌（NSCLC）患者在接受抗PD-1治疗后的免疫微环境异质性，以了解不同患者对治疗反应的差异。研究者们通过单细胞RNA测序（scRNA-seq）和T细胞受体测序（scTCR-seq）分析了234名接受新辅助化疗联合抗PD-1治疗的NSCLC患者的肿瘤样本。研究发现，这些患者可以分为五种不同的肿瘤免疫微环境（TIME）亚型，这些亚型与主要病理反应（MPR）率相关。具体来说，NK细胞、记忆B细胞和耗竭前体T细胞与MPR相关，而非MPR患者则表现出更高的CCR8+ Tregs水平。此外，T细胞克隆扩增特征分析揭示了非MPR患者中的异质性，表现为Tex相关细胞和CCR8+ Tregs的不同扩增程度。研究还发现，耗竭前体T细胞（Texp细胞）的比例与无复发生存期相关，能够识别出尽管未达到MPR但复发风险降低的患者亚组。这项研究提供了对化疗免疫治疗反应的TIME异质性分析，为NSCLC管理提供了新的见解。
Abstract:
Anti-PD-(L)1 treatment is standard for non-small cell lung cancer (NSCLC), but patients show variable responses to the same regimen. The tumor immune microenvironment (TIME) is associated with immunotherapy response, yet …
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Anti-PD-(L)1 treatment is standard for non-small cell lung cancer (NSCLC), but patients show variable responses to the same regimen. The tumor immune microenvironment (TIME) is associated with immunotherapy response, yet the heterogeneous underlying therapeutic outcomes remain underexplored. We applied single-cell RNA and TCR sequencing (scRNA/TCR-seq) to analyze surgical tumor samples from 234 NSCLC patients post-neoadjuvant chemo-immunotherapy. Analyses revealed five distinct TIME subtypes with varying major pathological response (MPR) rates. MPR patients had elevated levels of FGFBP2 NK/NK-like T cells, memory B cells, or effector T cells, while non-MPR patients showed higher CCR8 Tregs. T cell clonal expansion analyses unveiled heterogeneity in non-MPR patients, marked by varying expansions of Tex-relevant cells and CCR8 Tregs. Precursor exhausted T cells (Texp cells) correlated with recurrence-free survival, identifying a patient subgroup with reduced recurrence risk despite lack of MPR. Our study dissects TIME heterogeneity in response to chemoimmunotherapy, offering insights for NSCLC management.
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