只有少数三阴性乳腺癌患者可以从免疫检查点抑制剂（ICI）靶向PD-1/PD-L1信号通路与化疗联合治疗中受益。在这里，我们发现ICI加紫杉醇联合治疗的治疗反应与PD-L1的亚细胞重分布相关。在ICI加nab-紫杉醇免疫疗法队列中，来自响应者的肿瘤样本显示PD-L1在线粒体上的显着分布，而非响应者则显示PD-L1在肿瘤细胞膜上而不是在线粒体中的增加堆积。我们的结果还表明，PD-L1的分布模式由ATAD3A-PINK1轴调节。机制上，PINK1通过线粒体嗜食途径招募PD-L1到线粒体进行降解。重要的是，紫杉醇通过抑制PINK1依赖的线粒体嗜食作用，增加ATAD3A表达来破坏PD-L1的蛋白稳态，促进了PD-L1的肿瘤细胞膜积累。临床上，在ICI加紫杉醇治疗之前检测出ATAD3A高表达的肿瘤患者的无进展生存期明显缩短，与ATAD3A低表达的患者相比。预临床结果进一步证明，靶向ATAD3A重建有利的抗肿瘤免疫微环境，提高ICI加紫杉醇联合治疗的疗效。总之，我们的结果表明，ATAD3A不仅通过防止PD-L1线粒体分布而为ICI加紫杉醇联合治疗提供了耐药因素，而且还是增加化疗免疫疗法治疗反应的有前途的靶点。© 2023.作者（们）。

Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.© 2023. The Author(s).