Detection of cancer at an early stage when it is still localized improves patient response to medical interventions for most cancer types. The success of screening tools such as cervical cytology to reduce mortality has spurred significant interest in new methods for early detection (for example, using non-invasive blood-based or biofluid-based biomarkers). Yet biomarkers shed from early lesions are limited by fundamental biological and mass transport barriers — such as short circulation times and blood dilution — that limit early detection. To address this issue, synthetic biomarkers are being developed. These represent an emerging class of diagnostics that deploy bioengineered sensors inside the body to query early-stage tumours and amplify disease signals to levels that could potentially exceed those of shed biomarkers. These strategies leverage design principles and advances from chemistry, synthetic biology and cell engineering. In this Review, we discuss the rationale for development of biofluid-based synthetic biomarkers. We examine how these strategies harness dysregulated features of tumours to amplify detection signals, use tumour-selective activation to increase specificity and leverage natural processing of bodily fluids (for example, blood, urine and proximal fluids) for easy detection. Finally, we highlight the challenges that exist for preclinical development and clinical translation of synthetic biomarker diagnostics.

在癌症仍处于局部状态的早期阶段进行检测，可以提高患者对大多数癌症类型的医疗干预的反应。宫颈细胞学等筛查工具在降低死亡率方面的成功激发了人们对早期检测新方法的极大兴趣（例如，使用基于血液或生物液体的非侵入性生物标志物）。然而，从早期病变中脱落的生物标志物受到基本的生物和质量运输障碍的限制，例如循环时间短和血液稀释，这限制了早期检测。为了解决这个问题，正在开发合成生物标志物。这些代表了一类新兴的诊断方法，在体内部署生物工程传感器来查询早期肿瘤并将疾病信号放大到可能超过脱落生物标志物的水平。这些策略利用了化学、合成生物学和细胞工程的设计原理和进步。在这篇综述中，我们讨论了开发基于生物流体的合成生物标志物的基本原理。我们研究这些策略如何利用肿瘤失调的特征来放大检测信号，使用肿瘤选择性激活来提高特异性，并利用体液（例如血液、尿液和近端液体）的自然处理来轻松检测。最后，我们强调了合成生物标志物诊断的临床前开发和临床转化所面临的挑战。