摘要
众所周知,原癌基因及抑癌基因在细胞周期调控、增殖和凋亡等过程中发挥特定的功能,而癌症的发生发展与这些基因的异常改变密切相关,并且不同基因的改变会导致同种及不同癌症患者之间产生巨大的表型差异。近年来,免疫疗法的兴起为临床癌症患者带来了较好的治疗效果,但大部分患者仍面临着低应答以及耐药等问题。针对免疫疗法疗效较差的原因,研究人员进行了广泛研究。最终发现,原癌基因及抑癌基因异常表达对肿瘤免疫微环境的调控作用是导致免疫疗法无法达到预期疗效的重要因素之一。因此,探究不同基因改变对肿瘤微环境的影响可以更好地解决临床治疗过程中出现的问题,为患者提供更加精准的治疗方案。本文主要总结了几种常见原癌基因及抑癌基因突变对肿瘤微环境中抑制性免疫细胞、抗肿瘤免疫效应细胞以及肿瘤相关成纤维细胞的影响,阐明了肿瘤细胞中基因改变对肿瘤免疫微环境的调控和重塑作用,并针对肿瘤中基因改变的干预手段与免疫疗法联用的巨大潜力进行了分析,以期为癌症精准免疫治疗提供理论基础及发展策略。
In recent years,immunotherapy has become an excellent option for cancer patients,but most patients still face problems such as low response or drug resistance.Therefore,researchers conducted extensive studies on the reasons for the poor efficacy of immunotherapy.Eventually,it was found that the regulatory effect of abnormal expression of oncogenes and tumor suppressor genes on the tumor immune microenvironment is one of the important factors leading to the failure of immunotherapy to achieve the expected efficacy.It is well known that cancer is a kind of disease caused by the interaction between environmental and genetic factors,and the occurrence of cancer is mainly related to genetic alteration.Physiologically,the balance between oncogenes and tumor suppressor genes is crucial for DNA replication and proliferation regulation.However,under certain conditions,such as viral infection,chemical carcinogens or radiation,these genes may be mutated and eventually induce cancer.In addition,the combination of different gene mutations can also lead to significant differences among patients.For example,certain gene mutations are associated with the metastasis of cancer cells,while some are associated with the resistance of cancer cells to the attack of immune cells.Therefore,exploring the effects of different genetic alterations on the tumor microenvironment can help us better solve the problems in the process of clinical treatment and provide a theoretical basis for designing gene-targeted and personalized therapies.This review mainly summarizes the effects of common oncogenes and tumor suppressor gene mutations on immunosuppressive cells,anti-tumor immune effector cells and tumor-associated fibroblasts in the tumor microenvironment.Firstly,when the oncogene KRAS,c-Myc and EGFR are abnormally activated,cancer cell will secrete various cytokines and chemokines,thereby recruiting various immunosuppressive cells to the TME and causing exhaustion of CD8+T and NK cells.It can also reprogram CAFs and eventually promote the development of cancer.Furthermore,similar phenomena occur after the inactivation of tumor suppressor genes.For example,cancer cells with inactivated PTEN genes will secrete large amounts of IL-33 and LOX to recruit macrophages and induce TAMs.Cancer cells can secrete a variety of microRNAs into the tumor microenvironment after p53 dysregulation.These mircoRNAs can reprogram CAFs and lead to epithelial-mesenchymal transition.Finally,we summarize the reversing effects of therapeutic interventions targeting mutant oncogenes or tumor suppressor genes(such as KRAS inhibitors,overexpression of p53 by mRNA,PI3Kβinhibitors)on the immunosuppressive tumor microenvironment.Some of the results of their synergistic effects in combination with immunotherapy are also listed.Compared with monotherapy,the combination of either KRAS inhibitor or p53 mRNA nanomedicine withαPD-1 therapy resulted in more durable and potent anti-tumor effects.In summary,this review elucidates the regulatory and remodeling effects of genetic alterations in tumor cells on the tumor immune microenvironment,and analyzes the great potential of gene alteration intervention combined with immunotherapy.We hope it can provide theoretical basis and development strategy for precise cancer immunotherapy.
作者
谭舒祎
张建
TAN Shu-Yi;ZHANG Jian(Institute of Immunopharmaceutical Sciences,School of Pharmaceutical Sciences,Shandong University,Jinan 250012,China)
出处
《生物化学与生物物理进展》
北大核心
2025年第11期2700-2716,共17页
Progress In Biochemistry and Biophysics
基金
国家自然科学基金(82471763)资助项目。
关键词
肿瘤微环境
肿瘤免疫
癌基因
抑癌基因
tumor microenvironment
tumor immunology
oncogene
cancer suppressor gene
作者简介
通讯联系人:张建,Tel:0531-88383781,E-mail:zhangj65@sdu.edu.cn。
