大多数乳腺癌对免疫检查点抑制剂无响应，迫切需要寻找新的增敏策略。本研究发现，由TBK1适配蛋白AZI2介导的TBK-IFN途径的激活是实现这一目的的有效策略。我们的初步观察结果显示，RB1CC1缺失导致AZI2在斑点中累积，同时选择性巨噬细胞自噬/自噬货物受体也与其一起累积，这两者都是TBK1激活所需的。具体而言，破坏RB1CC1的选择性自噬功能足以维持AZI2斑点的积累和TBK1的激活。然后，AZI2介导DDX3X的下游激活，增加其与IRF3的相互作用，以转录促炎趋化因子。因此，我们进行了一项筛选实验，旨在寻找能够诱导AZI2-TBK1途径的抑制剂，结果发现Lys05是一种诱导促炎趋化因子表达和CD8+ T细胞浸润肿瘤的药物。总之，我们发现了一个与选择性自噬阻断响应的独特AZI2-TBK1-IFN信号通路，可以被激活以使乳腺癌更具免疫原性。

Most breast cancers do not respond to immune checkpoint inhibitors and there is an urgent need to identify novel sensitization strategies. Herein, we uncovered that activation of the TBK-IFN pathway that is mediated by the TBK1 adapter protein AZI2 is a potent strategy for this purpose. Our initial observations showed that RB1CC1 depletion leads to accumulation of AZI2, in puncta along with selective macroautophagy/autophagy cargo receptors, which are both required for TBK1 activation. Specifically, disrupting the selective autophagy function of RB1CC1 was sufficient to sustain AZI2 puncta accumulation and TBK1 activation. AZI2 then mediates downstream activation of DDX3X, increasing its interaction with IRF3 for transcription of pro-inflammatory chemokines. Consequently, we performed a screen to identify inhibitors that can induce the AZI2-TBK1 pathway, and this revealed Lys05 as a pharmacological agent that induced pro-inflammatory chemokine expression and CD8+ T cell infiltration into tumors. Overall, we have identified a distinct AZI2-TBK1-IFN signaling pathway that is responsive to selective autophagy blockade and can be activated to make breast cancers more immunogenic.