低氧肿瘤微环境的靶向治疗(Nature Reviews Clinical Oncology, IF:...

SCI

8 August 2021

_{Therapeutic targeting of the hypoxic tumour microenvironment}

• D. Singleton, A. Macann and W. Wilson

• CORRESPONDENCE TO: [e-mail]

Abstract 概要

Hypoxia is prevalent in human tumours and contributes to microenvironments that shape cancer evolution and adversely affect therapeutic outcomes. Historically, two different tumour microenvironment (TME) research communities have been discernible. One has focused on physicochemical gradients of oxygen, pH and nutrients in the tumour interstitium, motivated in part by the barrier that hypoxia poses to effective radiotherapy. The other has focused on cellular interactions involving tumour and non-tumour cells within the TME. Over the past decade, strong links have been established between these two themes, providing new insights into fundamental aspects of tumour biology and presenting new strategies for addressing the effects of hypoxia and other microenvironmental features that arise from the inefficient microvascular system in solid tumours. This Review provides a perspective on advances at the interface between these two aspects of the TME, with a focus on translational therapeutic opportunities relating to the elimination and/or exploitation of tumour hypoxia.

缺氧环境在人类肿瘤中很普遍，其塑造癌症进化的微环境并对治疗结果产生不利影响。既往研究中，两个不同的肿瘤微环境 (TME) 研究方向存在差异。其中一研究方向关注肿瘤细胞间质中氧、pH 值和营养物质的物理化学梯度，原因在于缺氧对肿瘤放疗有效治疗可造成障碍。另一研究方向则侧重于 TME 内肿瘤和非肿瘤细胞的细胞相互作用。过去的十年间，这两个方向之间联系牢固，在肿瘤生物学的基本研究方面提供了新的见解，并提出了新策略以解决实体肿瘤中低效微血管系统产生的低氧和其他特征微环境的影响。本综述讨论了 TME 两个方向之间交互的进展，重点介绍了消除和/或利用肿瘤缺氧因素转化治疗。

Key points 关键点

· O2 deficiency (euhypoxia), and mutations that have similar effects on patterns of gene expression (pseudohypoxia), have widespread effects on tumour evolution and sensitivity to anticancer agents. · Hypoxia-activated prodrugs have been widely investigated for targeting hypoxic tumour cells, but their clinical development has been compromised by a failure to assess hypoxia (and other relevant biomarkers) in individual tumours.

· Electron-affinic radiosensitizers mimic some of the effects of O2 in radiation biology and might have applications in highly hypofractionated radiotherapy protocols that are increasingly used to control oligometastatic disease.

· Hypoxia and associated features of the tumour microenvironment (adenosine, acidosis and nutrient deficiencies) are profoundly immunosuppressive; agents that alleviate hypoxia and/or acidosis can enhance the efficacy of immune-checkpoint inhibitors.

· New evidence demonstrates that suppression of O2 consumption using inhibitors of the mitochondrial electron transport chain can relieve tumour hypoxia in patients.

· Anticancer therapies that induce vascular damage can exacerbate tumour hypoxia, triggering a vascular repair process that supports tumour regrowth while also suppressing homology-directed repair of DNA damage. Both of these responses to treatment-induced hypoxia can be targeted therapeutically.

· O2 缺乏（真缺氧）和对基因表达模式有类似影响的突变（假性缺氧）对肿瘤进化和抗癌药物的敏感性具有广泛的影响。

· 低氧激活的前体药物已被广泛研究用于靶向低氧肿瘤细胞，但由于未能评估个别肿瘤中的低氧（和其他相关生物标志物），它们的临床开发受到了影响。

· 电子亲和放射增敏剂模拟了 O2在放射生物学中的一些影响，并且可能应用于大量低分割的放射治疗方案，此方案也越来越多地用于控制寡转移性疾病。

· 低氧肿瘤微环境和其他相关特征的肿瘤微环境（如：腺苷、酸中毒和营养缺乏）具有严重的免疫抑制作用；缓解低氧和/或酸中毒的药物可以增强免疫检查点抑制剂的功效。

· 新证据表明，使用线粒体电子传递链抑制剂抑制 O2 消耗可以缓解患者的肿瘤低氧。

· 诱导血管损伤的抗癌疗法会加剧肿瘤低氧，触发支持肿瘤再生的血管修复过程，同时抑制同源定向的 DNA 损伤修复。这两种对治疗诱导的低氧的反应都可以作为治疗靶点。