Mitochondrial TSPO Promotes Hepatocellular Carcinoma Progression through Ferroptosis Inhibition and Immune Evasion

Abstract

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.

CircRNA LOC729852 promotes bladder cancer progression by regulating macrophage polarization and recruitment via the miR‐769‐5p/IL‐10 axis

“…The MCL‐1 can be combined with Beclin 1 protein BH3 domain structure, thus inhibiting Beclin 1, autophagy and negative control cells 76–78 . In addition, the agglomeration of P62 and autophagy is directly related to, such as TSPO can through direct action with P62, lead to agglomeration of P62 and inhibition of autophagy 79 . In bladder cancer, CXCL12 upregulates the deubiquitinating enzyme CYLD through the JAK2/STAT3 signalling pathway, and CYLD inhibits autophagy in bladder cancer by inducing the accumulation of P62 through deubiquitination of P62 80 .…”

“… 76 , 77 , 78 In addition, the agglomeration of P62 and autophagy is directly related to, such as TSPO can through direct action with P62, lead to agglomeration of P62 and inhibition of autophagy. 79 In bladder cancer, CXCL12 upregulates the deubiquitinating enzyme CYLD through the JAK2/STAT3 signalling pathway, and CYLD inhibits autophagy in bladder cancer by inducing the accumulation of P62 through deubiquitination of P62. 80 In addition, through the JAK2/STAT3 signalling pathway inhibitor Stattic also can inhibit the rise in JAK2/STAT3 signal pathway of P62, 80 miR‐16‐5p can promote autophagy by upregulating Beclin 1 and downregulating P62, thus playing an inhibitory effect on bladder cancer.…”

Ferroptosis in lung cancer: dual role, multi-level regulation, and new therapeutic strategies

“…The difference may be mainly due to the opposite regulatory direction of the two, such as the former upregulates ferroptosis resistance genes and reduces the incidence of ferroptosis, thereby reducing the production of immunogenic cell death, reducing the immunogenicity of tumor, and escaping the killing of immune cells. Recently, it has been reported that Mitochondrial translocator protein promotes tumor cell immune escape by up-regulating PD-L1 expression through Nrf2-mediated transcription ( 76 ).…”

Multifunctional and stimuli-responsive liposomes in hepatocellular carcinoma diagnosis and therapy

“…Unfortunately, the aforementioned therapies demonstrate low ability in significantly improving survival and prognosis of patients [86] , urging scientists for developing new therapies for HCC. Moreover, in the recent years, immunotherapy has been significantly applied in the treatment of cancer [ 87 , 88 ] that it is of importance for HCC, but the immune evasion is a problem in HCC therapy [89] , [90] , [91] .…”