肿瘤细胞治疗研究
英文原题：Targeting MUC1-C Suppresses Chronic Activation of Cytosolic Nucleotide Receptors and STING in Triple-Negative Breast Cancer.
MUC1-C 顶端跨膜蛋白在上皮细胞对炎症的急性反应中被激活。
MUC1-C顶端跨膜蛋白在上皮细胞炎症急性应答中被激活。然而，MUC1-C持续活化会促进癌症进展，凸显其作为治疗靶点的重要性。我们报告，三阴性乳腺癌（TNBC）细胞内RIG-I、MDA5和cGAS胞质核苷酸模式识别受体（PRR），以及cGAS-干扰素基因刺激因子（STING）的本底表达均依赖MUC1-C。MUC1-C通过诱导PRR/STING轴，驱动持续产生IFN-β并激活I型干扰素（IFN）通路。因此，MUC1-C诱导IFN相关DNA损伤耐药基因特征（IRDS），其中包括ISG15，将慢性炎症与DNA损伤耐药联系起来。在卡铂或PARP抑制剂奥拉帕利处理的TNBC细胞中靶向MUC1-C进一步证明，PRR、STING和ISG15表达以及细胞本底DNA损伤耐药均依赖MUC1-C。从转化医学角度看，TNBC肿瘤中MUC1与STING和ISG15上调显著相关；MUC1也是CAR-T细胞、抗体药物偶联物（ADC）和直接抑制剂的治疗靶点，这些方法正在临床前和临床开发中。
The MUC1-C apical transmembrane protein is activated in the acute response of epithelial cells to inflammation. However, chronic MUC1-C activation promotes cancer progression, emphasizing the importance of MUC1-C as a target for treatment. We report here that MUC1-C is necessary for intrinsic expression of the RIG-I, MDA5 and cGAS cytosolic nucleotide pattern recognition receptors (PRRs) and the cGAS-stimulator of IFN genes (STING) in triple-negative breast cancer (TNBC) cells. Consistent with inducing the PRR/STING axis, MUC1-C drives chronic IFN- production and activation of the type I interferon (IFN) pathway. MUC1-C thereby induces the IFN-related DNA damage resistance gene signature (IRDS), which includes ISG15, in linking chronic inflammation with DNA damage resistance. Targeting MUC1-C in TNBC cells treated with carboplatin or the PARP inhibitor olaparib further demonstrated that MUC1-C is necessary for expression of PRRs, STING and ISG15 and for intrinsic DNA damage resistance. Of translational relevance, MUC1 significantly associates with upregulation of STING and ISG15 in TNBC tumors and is a target for treatment with CAR T cells, antibody-drug conjugates (ADCs) and direct inhibitors that are under preclinical and clinical development.
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