Laboratory of Radiation Biology, Laboratory Medicine Center, Department of Blood Transfusion, The Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China.
Institute of Cancer, The Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China.
Cells. 2021 Apr 14;10(4):903. doi: 10.3390/cells10040903.
Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous "camouflage" in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages' ontogeny in macrophages' functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs' origins may help understand the classification of TAMs' population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.
巨噬细胞广泛分布于组织中，在维持内环境稳定方面发挥作用。在癌症发展过程中，肿瘤相关巨噬细胞（TAMs）通过促进肿瘤增殖、血管生成、转移和免疫抑制，主要支持疾病进展和对治疗的耐药性，因此成为肿瘤免疫治疗的靶点。在这里，我们首先指出 TAMs 在表型和功能上具有高度的可塑性和异质性，能够对微环境信号做出反应。我们指出，努力揭开 TAMs 异质性的“伪装”，有助于有效地靶向实际上促肿瘤的 TAMs。特别是，几种命运图谱模型表明，大多数组织驻留巨噬细胞（TRMs）是由胚胎祖细胞产生的，新的范例揭示了 TAMs 的发生。首先，来自胚胎模型的 TRMs 和循环单核细胞的 TAMs 具有不同的转录谱和功能，这表明 TAMs 的发生是 TAMs 功能异质性的原因之一，除了微环境信号之外。其次，代谢重编程有助于确定 TAMs 表型和功能特征的机制，包括代谢偏向，这是在生理和病理条件下，巨噬细胞从胚胎发生到巨噬细胞功能可塑性的过程中产生的。这两种模型都旨在剖析 TAMs 表型和功能异质性中与发生相关的代谢调控。我们认为，从单细胞转录组学对亚克隆 TAMs 起源的研究中，可以帮助理解 TAMs 群体在亚克隆进化中的分类及其在肿瘤发展中的不同作用。我们设想，TAM 亚克隆特异性的代谢重编程可能会与未来的癌症治疗相结合。
