肝细胞癌（HCC）自2017年起已成为免疫治疗的批准指征，但预测疗效的生物标志物仍然有限。了解和描述肿瘤免疫微环境能更好地对这些肿瘤进行分类，并可能揭示预测免疫治疗效果的生物标志物。本论文中，我们应用了细胞类型解析算法和DNA甲基化芯片数据，研究了HCC肿瘤微环境的组成。利用两个公开可用的数据集，共收集了57例患者的肿瘤和正常组织样本，我们发现了免疫细胞组成方面的关键差异。我们发现与相邻正常组织相比，HCC肿瘤中NK细胞的丰度显著降低。我们还应用了DNA甲基化“时钟”，用于估计表型老化，并将这些结果与基于表达的细胞衰老测定进行比较。我们发现HCC肿瘤的衰老和表观遗传老化明显增加，而加速老化和衰老程度与NK细胞丰度显著相关。总而言之，我们发现肿瘤微环境中的NK细胞浸润显著减少，并且这种NK细胞丧失与增加的衰老和与年龄相关的表型密切相关。这些发现指出了NK细胞与衰老的肿瘤微环境之间的关键相互作用，并为HCC的发病机制以及潜在的治疗效果生物标志物提供了见解。

Hepatocellular carcinoma (HCC) has been an approved indication for the administration of immunotherapy since 2017, but biomarkers that predict therapeutic response have remained limited. Understanding and characterizing the tumor immune microenvironment enables better classification of these tumors and may reveal biomarkers that predict immunotherapeutic efficacy. In this paper, we applied a cell-type deconvolution algorithm using DNA methylation array data to investigate the composition of the tumor microenvironment in HCC. Using two publicly available datasets with a total cohort size of 57 patients, each with tumor and matched normal tissue samples, we identified key differences in immune cell composition. We found that NK cell abundance was significantly decreased in HCC tumors compared to adjacent normal tissue. We also applied DNA methylation "clocks" which estimate phenotypic aging and compared these findings to expression-based determinations of cellular senescence. Senescence and epigenetic aging was significantly increased in HCC tumors, and the degree of age acceleration and senescence was strongly associated with decreased NK cell abundance. In summary, we found that NK cell infiltration in the tumor microenvironment is significantly diminished, and that this loss of NK abundance is strongly associated with increased senescence and age-related phenotype. These findings point to key interactions between NK cells and the senescent tumor microenvironment and offer insights into the pathogenesis of HCC as well as potential biomarkers of therapeutic efficacy.