The tumor microenvironment (TME) comprises complex interactions of multiple cell types that determines cell behavior and metabolism such as nutrient competition and immune suppression. We discuss the various types of heterogeneity that exist in solid tumors, and the complications this invokes for studies of TME. As human subjects and in vivo model systems are complex and difficult to manipulate, simpler 3D model systems that are compatible with flexible experimental control are necessary for studying metabolic regulation in TME. Stable Isotope Resolved Metabolomics (SIRM) is a valuable tool for tracing metabolic networks in complex systems, but at present does not directly address heterogeneous metabolism at the individual cell level. We compare the advantages and disadvantages of different model systems for SIRM experiments, with a focus on lung cancer cells, their interactions with macrophages and T cells, and their response to modulators in the immune microenvironment. We describe the experimental set up, illustrate results from 3D cultures and co-cultures of lung cancer cells with human macrophages, and outline strategies to address the heterogeneous TME.

中文翻译：

---

从稳定同位素解析代谢组学角度解决肿瘤微环境实验模型中的代谢异质性。

肿瘤微环境（TME）包含多种细胞类型的复杂相互作用，这些相互作用决定了细胞行为和新陈代谢，例如营养竞争和免疫抑制。我们讨论了实体瘤中存在的各种异质性，以及由此引起的TME研究的并发症。由于人类受试者和体内模型系统复杂且难以操作，因此与灵活的实验控制相兼容的更简单的3D模型系统对于研究TME中的代谢调控至关重要。稳定同位素分解代谢组学（SIRM）是追踪复杂系统中代谢网络的有价值的工具，但目前尚不能直接解决单个细胞水平上的异质代谢。我们针对SIRM实验比较了不同模型系统的优缺点，主要研究肺癌细胞，它们与巨噬细胞和T细胞的相互作用以及对免疫微环境中调节剂的反应。我们描述了实验设置，说明了肺癌细胞与人类巨噬细胞的3D培养和共培养的结果，并概述了解决异质TME的策略。