申请人10多年来聚焦“肝癌异质性与个体化治疗”开展系列研究，以第一/通讯作者发表SCI 论文30篇，IF累计190.2分，引用1045次，入选中组部青年拔尖人才计划、全国青年岗位能手、全国优秀博士论文。在前期基础上，本项目基于大量肝癌患者来源的、真实反应患者生物多样性的PDC和PDX模型，并首创来源于同一患者、保留癌内异质性的“PDC群”和“PDX群”，借助于高通量无偏倚的基因组注释和药物筛选，首次尝试建立反应药效的患者分子分型和个性化联合用药模式，以期解决个体间异质性和癌内异质性的困扰。并利用遗传变异所产生的个体特异性抗原，尝试以“抗原特异性T细胞”为有益的补充。进而在“药效标志物”基础上，指导肝癌 “小型化“和“精准化”靶向治疗的临床试验，改变肝癌临床试验屡战屡败的局面。本项目的实施，对理解肝癌个体肿瘤发展史、降低抗药性及实现真正意义上的个体化联合治疗，具有重要的理论和临床指导意义。

I, the applicant, have been focused on the tumor heterogeneity and personalized treatment in hepatocellular carcinoma (HCC) during the last decade. In total, I have published 30 high-quality SCI papers as the first or corresponding author, whose impact factors aggregate 190.2 and have been cited by about 1,045 publications. It is a great honor that I was awarded as the Top Youth Talent Program by the Organization Department of CCCPC, the National Youth Job Expert, and the National Excellent Doctorial Dissertation. In this study, we are aimed to establish a molecular and pharmacologic stratification of HCC patients, and identify personalized combinational treatment modalities for individual HCCs. Previously, we have established a large number of PDCs (Patient Derived Cell lines) and PDXs (Patient Derived Xenografts) from HCC patients, retaining the intertumor heterogeneity in HCC. Notably, for the first time, we established "PDC groups" and "PDX groups" derived from multiregion spatially distinct tumor tissues for each patient, recapitulating the intratumor heterogeneity in HCC. Herein, our genomic profiling and pharmacologic screening on these PDC and PDX models would provide a valuable opportunity to overcome the therapeutic resistance due to the intratumor and intertumor heterogeneity. Meanwhile, we aim to identify tumor-specific antigens resulted from genetic alterations in each HCC, and to generate the tumor-antigen specific autologous T cells. The adoptive immune therapy based on these autologous T cells would serve as an indispensible alternative treatment for individual patients. Finally, by novel clinical trials that consider clonal diversity, we will validate the efficacy of unexpected combination therapies and provide evidence for adaptive therapy to avoid the selection of drug-resistant subclones. In summary, this study, through resolving the spatial and temporal heterogeneity of subclones with drug responses, may offer new insights into therapy response, tumor evolutionary histories and clinical trial design in HCC.