肝细胞癌（HCC）免疫治疗的功效受限于肿瘤浸润T细胞的有限反应性和短暂持续时间。这些缺陷可能归因于T细胞的增殖能力。本研究的主要目标是确定在HCC微环境中调控肿瘤浸润淋巴细胞（TIL）增殖的关键因子。通过利用组织浸润的T细胞蛋白组学和分数蛋白组学，我们分析了HCC、肝纤维化和血管瘤（作为对照组）群体中T细胞的差异蛋白。此外，我们还研究了HCC和志愿者健康（作为对照组）群体中T细胞的差异调控转录因子。通过利用cyTOF和流式细胞术技术，以及产生CD8+ T特异性BMI1基因敲除小鼠，我们确认了BMI1对CD127+KLRG1+记忆细胞分化的调控。通过RNA-seq和MeRIP-seq，我们验证了BMI1独立于其经典功能调控TCF1表达。此外，通过进行酪胺酸酶信号放大（TSA）免疫组织化学分析，利用水动力学小鼠HCC模型，以及利用肝脏特异性纳米颗粒靶向治疗，我们证明了HCC中的BMI1影响CD8+T浸润细胞的增殖。BMI1抑制促进效应T细胞分化同时抑制记忆T细胞分化。此外，肝脏特异性的BMI1基因沉默有助于改善T细胞功能障碍并减缓HCC进展。我们的研究小组开创性地探索了HCC浸润T细胞的蛋白组学，揭示了BMI1在控制CD127+KLRG1+记忆CD8+T细胞分化中的关键作用，这是实现HCC免疫治疗效果的基石。 版权所有 © 2023 Elsevier B.V. 发布。

The efficacy of HCC (hepatocellular carcinoma) immunotherapy is hindered by the limited reactivity and short duration of tumor-infiltrating T cells. These deficiencies may be ascribed to the proliferative ability of T cells. The primary objective of this study was to identify the key factor regulating tumor-infiltrating lymphocytes (TIL) proliferation within the HCC microenvironment. Through the utilization of tissue-infiltrated T cell proteomics and fraction proteomics, we analyzed the differential proteins in T cells among HCC, liver fibrosis, and hemangioma (serving as controls) groups. Additionally, we examined the differential regulatory TFs of T cells between the HCC and VH (volunteer healthy, as a control) groups. Using cyTOF and flow cytometry technologies, as well as generating CD8+ T-specific BMI1 knockout mice, we confirmed that BMI1 controls CD127+KLRG1+ memory cell differentiation. Through RNA-seq and MeRIP-seq, we verified that BMI1 regulates TCF1 expression independently of its classical function. Furthermore, by conducting Tyramide signal amplification (TSA) IHC analysis, employing a hydrodynamic mouse HCC model, and utilizing liver-specific nanoparticle targeting therapy, we demonstrated that BMI1 in HCC influences the proliferation of infiltrating CD8+T. BMI1 inhibition promotes effector T cell differentiation while suppressing memory T cell differentiation. Moreover, liver-specific BMI1 knockdown proves beneficial in ameliorating T cell dysfunction and decelerating HCC progression. Our research group has pioneered the exploration of the proteomics of HCC-infiltrated T cells, shedding light on the pivotal role of BMI1 in controlling CD127+KLRG1+ memory CD8+ T cell differentiation, which serves as the cornerstone for achieving immunotherapy efficacy in HCC.Copyright © 2023. Published by Elsevier B.V.