Metastasis is responsible for the majority of death in cancer patients. Of the different steps in the metastasis cascade, the postdissemination phase is perhaps one of the least understood. Many factors, both from the disseminated tumor cells and the microenvironment, impact the success of the metastatic outgrowth. In this article, we discuss the interactions between colonizing cancer cells and immune cells in the period between vascular arrest in a secondary organ and metastatic outgrowth. We address the ambiguity in the findings of current research regarding the role of immune cells in regulating the metastatic microenvironment, and their hand in determining cancer cell fate.

Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of >100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and revealed stromal immunosuppressive states enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits.