放疗免疫调节效应研究的进展——从基础到临床

王妤; 毕楠

doi:10.19401/j.cnki.1007-3639.2023.12.003

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放疗免疫调节效应研究的进展——从基础到临床

综述 | 更新时间：2025-12-31

- 放疗免疫调节效应研究的进展——从基础到临床
- Advancements in the research of immunomodulatory effects of radiation therapy: from basic to clinical
- 中国癌症杂志 2023年33卷第12期页码：1083-1091
- 作者机构：
  
  国家癌症中心，国家肿瘤临床医学研究中心，中国医学科学院/北京协和医学院肿瘤医院放疗科，北京 100021
- 作者简介：
  
  [ "王妤（ORCID: 0009-0008-1769-9387），在读博士研究生，住院医师。" ]
  毕楠（ORCID: 0000-0001-7201-2930），主任医师。
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2023.12.003
  中图分类号： R730.5
- 收稿：2023-08-17，
  
  修回：2023-10-24，
  
  纸质出版：2023-12-30
- 稿件说明：
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王妤, 毕楠. 放疗免疫调节效应研究的进展——从基础到临床[J]. 中国癌症杂志, 2023,33(12):1083-1091.

Yu WANG, Nan BI. Advancements in the research of immunomodulatory effects of radiation therapy: from basic to clinical[J]. China Oncology, 2023, 33(12): 1083-1091.
王妤, 毕楠. 放疗免疫调节效应研究的进展——从基础到临床[J]. 中国癌症杂志, 2023,33(12):1083-1091. DOI： 10.19401/j.cnki.1007-3639.2023.12.003.

Yu WANG, Nan BI. Advancements in the research of immunomodulatory effects of radiation therapy: from basic to clinical[J]. China Oncology, 2023, 33(12): 1083-1091. DOI： 10.19401/j.cnki.1007-3639.2023.12.003.

摘要

既往观点认为，放射治疗主要通过破坏肿瘤细胞脱氧核糖核酸双链直接发挥杀伤肿瘤细胞的作用，近年来研究发现，放疗也可通过上调局部与全身免疫反应，间接产生积极有效的抗肿瘤免疫应答。然而，放疗的免疫调节效应具有双面性，一方面可激活并产生抗肿瘤免疫促进效应，另一方面也可能产生免疫抑制作用。其中，放疗正向调节适应性与固有性抗肿瘤免疫反应的关键分子机制主要包括：诱导免疫原性细胞凋亡从而促进T淋巴细胞的增殖与活化；激活环磷酸鸟苷-腺苷合成酶-干扰素基因刺激蛋白通路引发Ⅰ型干扰素反应；改变肿瘤细胞表型，加强其免疫原性与抗原可视度；刺激肿瘤细胞与基质细胞释放多种炎症因子，重塑肿瘤免疫微环境；上调肿瘤细胞表面免疫检查点以及死亡受体等的表达，促进免疫识别与抗肿瘤免疫应答。而放疗负向抑制免疫反应的主要机制包括：诱导肿瘤细胞上调多种免疫抑制因子的基因表达；增强包括调节性T细胞、髓系来源抑制性细胞在内的多种免疫抑制细胞的功能与作用；导致淋巴细胞的数量减少以及免疫效应细胞的耗竭等。基于以上关于放疗免疫调节效应的机制原理探索，目前在放疗联合免疫治疗的临床实践中也显示出重大的研究进展，包括免疫治疗时代背景下的放疗远隔效应，即放疗照射野以外产生的有效抗肿瘤免疫应答，以及立体定向放疗或低剂量放疗联合免疫检查点抑制剂治疗时显著增加的疗效获益。然而，目前对于放疗联合免疫治疗产生的协同作用机制及其具体影响因素等仍不明确，未来需要在放疗与免疫治疗联合治疗的最佳放疗剂量、放疗分割模式、放疗照射部位与靶区设计、免疫药物选择以及放疗与免疫联合治疗顺序等研究方向开展深入探索，以进一步提高临床疗效，促进放疗免疫调节生物学效应的临床转化应用。本文将对放疗的免疫调节效应以及放疗与免疫治疗联合协同作用的基础与临床研究最新进展进行系统综述，以期为放疗联合免疫治疗的理论基础发展与临床实践进步提供参考。

Abstract

Previously

radiotherapy was considered to directly kill tumor cells by deoxyribonucleic acid double-strand break. Recent studies have found that radiotherapy can also produce positive and effective anti-tumor effect by upregulating local and systemic immune responses. However

the immunomodulatory effect of radiotherapy is double-sided. On the one hand

it can activate anti-tumor immune-promoting effect

on the other hand

it may also produce immunosuppressive effect. The key molecular mechanisms of the positive regulation of adaptive and innate anti-tumor response by radiotherapy primarily include: induction of immunogenic cell death to promote the proliferation and activation of T lymphocytes; activation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway to induce type Ⅰ interferon response; changing the phenotype of tumor cells to enhance their immunogenicity and antigen visibility; stimulating tumor cells and stromal cells to release a variety of inflammatory factors and reshape the tumor immune microenvironment; upregulating the expression of immune checkpoint and death receptor on the surface of tumor cells to promote immune recognition and anti-tumor immune response. In addition

the mechanisms of negative immune suppression by radiotherapy mainly include: induction of tumor cells to upregulate the gene expression of multiple immunosuppressive factors; enhancing the function and effect of various immunosuppressive cells

including regulatory T cells and myeloid-derived suppressor cells; leading to the decreased number of lymphocytes and the depletion of immunologic effector cells. Based on the above exploration of the mechanisms and principle of the immunomodulatory effect of radiotherapy

significant progress has also been shown in the clinical practice of combining radiotherapy with immunotherapy

such as the abscopal effect in the context of immunotherapy era

that is

the effective anti-tumor immune responses generated outside the irradiation field of radiotherapy

as well as the increased efficacy benefit when stereotactic body radiation therapy or low-dose radiotherapy combined with immune checkpoint inhibitors. However

at present

the synergistic mechanism of radiotherapy plus immunotherapy and its influencing factors are unclear. In the future

more in-depth investigations on optimal radiotherapy dose

segmentation regimens

irradiation sites and target volume design

immunotherapy agent selection and the sequence of combining radiotherapy with immunotherapy are necessary

in order to further improve efficacy and promote the translational application of immunomodulatory biological effects of radiotherapy. This article systematically reviewed the latest advancements of basic and clinical research on the immunomodulatory effect of radiotherapy and the synergy of combing radiotherapy with immunotherapy

aiming to provide guidance on the development of theoretical basis and clinical practice regarding the combination of radiotherapy and immunotherapy.

关键词

Keywords

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