MET通过MTOR介导的自噬调节肝癌免疫原性和治疗抗性的作用及机制研究

Liver cancer seriously endangers human health, but currently there is still a lack of specific and effective therapeutic methods, and thus how to activate anti-tumor immune response has become the core problem of overcoming liver cancer. More and more evidence shows that in addition to supplementing nutrients and energy for tumor growth and survival, autophagy can also affect the therapeutic efficacy by regulating tumor immunogenicity and its microenvironment. Our recent studies have demonstrated that the HGF-MET signaling inactivation-caused conversion between tumor metabolism and autophagy is one of the main reasons for liver cancer resisting to targeted therapy; moreover, preliminary results further indicate that MET is a critical component of MTOR complex, and able to mediate MTOR activation via direct interaction with lysosomal V-ATPase. As well-known, MTOR is not only an important regulatory factor of autophagy machinery, but also closely related to the immunomodulation in tumor immune microenvironment, suggesting that the targeting of MET-MTOR-mediated autophagy is most likely the key to immunological suppression of liver cancer. Therefore, based on our previous studies, this project intends to deeply analyze the molecular mechanism of MET-MTOR axis in regulating liver cancer autophagy, immunogenicity and therapeutic resistance, and systematically elucidate the significance of MET-MTOR-autophagy pathway in liver cancer immunotherapy, so as to provide breakthrough ideas and solid theoretical basis for the prevention and treatment of liver cancer.

肝癌严重危害人类的健康，但目前依然缺乏特异而有效的治疗方法，如何激活机体的抗肿瘤免疫反应成为攻克肝癌的核心问题。越来越多的证据显示，自噬除了能为肿瘤的生长存活补充物质能量，还可以通过调节肿瘤的免疫原性及其微环境来影响治疗效果。我们近期的研究证实，HGF-MET信号通路失活所造成的肿瘤代谢与自噬间的转换是肝癌对靶向治疗产生拮抗的主要原因之一，且已有初步结果表明MET是MTOR复合物的核心组分，能直接结合溶酶体V-ATP酶来调节MTOR的活性。MTOR不仅是自噬中的重要调控因子，还与肿瘤及其微环境中的免疫调节密切相关，这提示我们靶向MET-MTOR介导的自噬极有可能是免疫抑制肝癌的关键。因此，本项目拟在前期研究的基础上，深入解析MET通过MTOR调节肝癌自噬、免疫原性及抗药性的分子机制，系统阐明MET-MTOR-自噬通路在肝癌免疫治疗中的意义，以期为肝癌的防治提供突破性的思路和坚实的理论依据。

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