肝细胞癌（HCC）是一种预后不良的最常见恶性疾病，迫切需要新的治疗策略。线粒体是细胞内稳态的关键调节因子和肿瘤治疗的潜在靶点。本文研究了线粒体转位蛋白（TSPO）在铁瘤和抗肿瘤免疫中的调节作用，评估了其对HCC的潜在治疗意义。TSPO在HCC中高表达并与预后不良相关。基因增强和缺失实验表明，TSPO促进HCC细胞在体内和体外的生长、迁移和侵袭。此外，TSPO通过增强Nrf2依赖的抗氧化防御系统，在抑制HCC细胞铁瘤中起调节作用。在机制上，TSPO直接与P62相互作用并干扰自噬，导致P62的积累。P62的积累与KEAP1竞争，阻止它将Nrf2作为蛋白酶降解的靶点。此外，TSPO通过Nrf2介导的转录途径上调PD-L1表达，从而促进HCC的免疫逃避。值得注意的是，TSPO抑制剂PK11195与抗PD-1抗体联合使用在小鼠模型中呈现出协同的抗肿瘤效果。总体而言，研究结果说明线粒体TSPO通过抑制铁瘤和抗肿瘤免疫促进了HCC的进展。针对TSPO可以是一种有前途的新的HCC治疗策略。© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis, and novel treatment strategies are urgently needed. Mitochondria are key regulators of cellular homeostasis and potential targets for tumor therapy. Here, the role of mitochondrial translocator protein (TSPO) in the regulation of ferroptosis and antitumor immunity is investigated and the potential therapeutic implications for HCC are assessed. TSPO is highly expressed in HCC and associated with poor prognosis. Gain- and loss-of-function experiments present that TSPO promotes HCC cell growth, migration, and invasion in vitro and in vivo. In addition, TSPO inhibits ferroptosis in HCC cells via enhancing the Nrf2-dependent antioxidant defense system. Mechanistically, TSPO directly interacts with P62 and interferes with autophagy, leading to the accumulation of P62. The P62 accumulation competes with KEAP1, preventing it from targeting Nrf2 for proteasomal degradation. Furthermore, TSPO promotes HCC immune escape by upregulating PD-L1 expression through Nrf2-mediated transcription. Notably, TSPO inhibitor PK11195 combines with anti-PD-1 antibody showing a synergistic anti-tumor effect in a mouse model. Overall, the results demonstrated that mitochondrial TSPO promotes HCC progression by inhibiting ferroptosis and antitumor immunity. Targeting TSPO can be a promising new strategy for HCC treatment.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.