柳叶刀肿瘤综述-癌症神经科学的治疗途径：转化前沿和临床机会

 经典高分文献阅读·柳叶刀肿瘤综述-癌症神经科学的治疗途径：转化前沿和临床机会 

Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities

癌症神经科学的治疗途径：转化前沿和临床机会

ABSTRACT

With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour–nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.

近年来，随着对肿瘤微环境的重要作用的日益关注，神经系统已成为癌症生长的新的和重要的促进因素。在这篇综述中，我们描述了基础、转化和临床进展，说明了神经如何促进肿瘤增殖、压力适应、免疫调节、转移、电活动过度和癫痫发作以及神经性疼痛. 总的来说，这个不断扩大的知识库揭示了癌症神经科学的多种治疗途径，值得在临床研究中进一步探索。我们讨论了可用的临床数据，包括正在进行的研究针对肿瘤-神经轴的新型药物的试验，以及将现有神经活性药物重新用作抗癌方法的治疗潜力，特别是与已建立的治疗方案相结合。最后，我们讨论了这些治疗策略的临床挑战，并强调了癌症神经科学新兴领域中未解决的问题和未来方向。

（一）Therapeutic avenues for cancer neuroscience

A surge of preclinical and clinical evidence in the past two decades has begun to elucidate the role of the nervous system in promoting cancer growth. In light of the many mechanisms of tumour–nerve crosstalk and their accompanying clinicopathological ramifications, we have organised their translational implications into six broad avenues of intervention: inhibiting tumour growth, combating treatment resistance and tumour adaptation to stress, enhancing anti-tumour immunity, preventing dissemination and metastasis, and managing morbidity by dampening electrical hyperactivity and seizures as well as neuropathic pain (figure 1). We will highlight the potential therapeutic opportunities and challenges galvanised by preclinical and preliminary clinical data.

（一）癌症神经科学的治疗途径

在过去的二十年中，大量的临床前和临床证据已经开始阐明神经系统在促进癌症生长中的作用。鉴于肿瘤-神经串扰的许多机制及其伴随的临床病理学后果，我们将它们的转化意义组织为六种广泛的干预途径：抑制肿瘤生长、对抗治疗耐药性和肿瘤对压力的适应、增强抗肿瘤免疫力、预防传播和转移，并通过抑制电活动过度和癫痫发作以及神经性疼痛来控制发病率（图 1）。我们将强调由临床前和初步临床数据激发的潜在治疗机遇和挑战。

1.Inhibiting tumour growth via modulation of the nervous system

2.Combating treatment resistance by disrupting stressadaptive mechanisms

3.Remodelling the immune microenvironment in combination with immunotherapy

4.Targeting metastatic spread

5.Disrupting electrical hyperactivity for dual control of tumour growth and seizures

6.Management of neuropathic pain by targeting the sensory nervous system

Figure 1: Six therapeutic avenues of cancer neuroscience

TCA=tricyclic antidepressant. SSRI=selective serotonin reuptake inhibitor. GFRα=glial cell line-derived neurotrophic factor family receptor alpha. ADC=antibody–drug conjugate. BDNF=brain-derived neurotrophic factor. NGF=nerve growth factor.

Figure 2. Example mechanisms of therapeutic avenues of cancer neuroscience

NGF=nerve growth factor. DRG=dorsal root ganglia. PDAC=pancreatic ductal adenocarcinoma

（二）Future therapeutic perspectives and challenges

As the tumour microenvironment has become increasingly appreciated as a major driver of cancer biology, the nervous system has emerged as a crucial component. The progress in both preclinical and clinical cancer neuroscience has increased exponentially in recent years and enhanced our mechanistic understanding of tumour–nerve crosstalk such that molecularly-targeted strategies are now poised for impactful clinical implementation. Three broad questions that remain incompletely answered include (1) whether the tumour–nerve axis can be successfully targeted with sufficient specificity for broad clinical benefit, (2) how neural regulation can synergistically integrate into existing treatment regimens, and (3) whether histopathological or other companion diagnostics can identify patients who are most likely to benefit from these therapeutic strategies.

（二）未来的治疗前景和挑战

随着肿瘤微环境作为癌症生物学的主要驱动因素越来越受到重视，神经系统已成为一个关键组成部分。近年来，临床前和临床癌症神经科学的进展呈指数级增长，增强了我们对肿瘤-神经串扰的机制理解，因此分子靶向策略现在已准备好进行有效的临床实施。三个尚未完全回答的广泛问题包括（1）是否可以成功地靶向肿瘤神经轴并具有足够的特异性以获得广泛的临床益处，（2）神经调节如何可以协同整合到现有的治疗方案中，以及 (3) 组织病理学或其他伴随诊断是否可以识别最有可能从这些治疗策略中受益的患者。

总结语：

The nascent field of cancer neuroscience is growing rapidly, with parallel efforts in uncovering the mechanistic underpinnings of tumour–nerve interactions and developing novel therapies through collaborative academic and commercial efforts. Lessons learned from the tumour microenvironment suggest that disrupting tumour–nerve dialogue could eventually become a mainstay of clinical oncology, akin to anti-angiogenic and immunomodulatory therapies nowadays.

癌症神经科学的新兴领域正在迅速发展，同时努力揭示肿瘤-神经相互作用的机制基础，并通过学术和商业合作开发新疗法。从肿瘤微环境中吸取的教训表明，破坏肿瘤-神经对话最终可能成为临床肿瘤学的支柱，类似于当今的抗血管生成和免疫调节疗法。

供文：Riozhou

排版：叮当丸子麻