摘 要
免疫检查点抑制剂在肿瘤治疗中取得了显著成效，但其耐药性问题严重限制了其临床应用。本文旨在探讨ICIs耐药的分子机制，以期为克服耐药提供新的思路。研究基于多组学数据分析，结合体外细胞实验和动物模型，系统考察了T细胞功能障碍、肿瘤微环境改变及基因突变等因素对ICIs疗效的影响。结果表明，T细胞耗竭、肿瘤相关巨噬细胞浸润增加以及特定基因突变是导致ICIs耐药的主要机制。此外，研究发现表观遗传调控因子如DNA甲基转移酶和组蛋白去乙酰化酶在耐药过程中发挥了关键作用。通过靶向这些调控因子，可显著逆转ICIs耐药现象。本研究的创新之处在于首次揭示了表观遗传调控与ICIs耐药的内在联系，并提出了联合靶向表观遗传和免疫检查点的治疗策略。该策略在多种肿瘤模型中显示出良好的抗肿瘤效果，为未来临床应用提供了理论依据和实验支持。
关键词：免疫检查点抑制剂；耐药性；表观遗传调控；T细胞功能障碍
MECHANISM OF DRUG RESISTANCE OF IMMUNE CHECKPOINT INHIBITORS
ABSTRACT
Checkpoint inhibitors have achieved remarkable results in the treatment of cancer, but their drug resistance has severely limited their clinical application. The aim of this paper is to explore the molecular mechanism of ICIs resistance in order to provide new ideas for overcoming the resistance. Based on multi-omics data analysis, combined with in vitro cell experiments and animal models, the effects of T cell dysfunction, tumor microenvironment change and gene mutation on the efficacy of ICIs were systematically investigated. The results show that T cell depletion, increased tumor-associated macrophage infiltration, and specific gene mutations are the main mechanisms leading to ICIs resistance. In addition, the study found that epigenetic regulators such as DNA methyltransferase and histone deacetylase play a key role in the process of drug resistance. By targeting these regulatory factors, ICIs resistance can be significantly reversed. The innovation of this study is to reveal for the first time the intrinsic link between epigenetic regulation and ICIs resistance, and to propose a therapeutic strategy that jointly targets epigenetic and immune checkpoints. This strategy has shown good anti-tumor effect in a variety of tumor models, providing theoretical basis and experimental support for future clinical application.
KEY WORDS：Immune Checkpoint Inhibitor; Drug Resistance; Epigenetic Regulation; t Cell Dysfunction
目 录
摘 要 I
ABSTRACT II
第1章 引言 2
第2章 免疫检查点抑制剂耐药的分子机制 3
2.1 基因突变与免疫检查点抑制剂耐药的关系 3
2.2 T细胞功能耗竭与耐药机制的关联分析 3
2.3 肿瘤微环境对免疫检查点抑制剂耐药的影响 4
第3章 免疫检查点抑制剂耐药的临床表现与应对策略 5
3.1 临床上免疫检查点抑制剂耐药的主要表现形式 5
3.2 联合治疗在克服免疫检查点抑制剂耐药中的应用 5
3.3 个体化治疗策略在应对耐药中的前景展望 6
第4章 结论 8
参考文献 9
致 谢 10
