Fig. 1: Overview of metastasis.

Metastasis is a complex multistep process, and the very concept of designing a metastasis-specific therapeutic must consider which part of the process is best to target. Given that metastases are derived mainly from invasive tumours, therapeutic efforts have often targeted the intrinsic invasive propensity of tumour cells^150,151. Tumour cell production of angiogenic factors and TGFβ can activate endothelial cells and fibroblasts to remodel tissues and promote tumour cell invasion of stromal-modified spaces¹⁵². Targeting stromal elements in cancers remains an active area of research^{153,154,155,156,157}. Intravasation of tumour cells is promoted by binding to macrophages that cause transient permeability in the vasculature¹⁵⁸; thus, targeting tumour-associated macrophages might reduce the number of circulating tumour cells (CTCs)¹⁵⁹. Multiple factors intrinsic to tumour cells (including epithelial-to-mesenchymal transition, production of proteases and migratory capacity) improve intravasation, often via effects on cell types including fibroblasts, neutrophils and macrophages¹⁶⁰. Most tumour cells that enter the vasculature die as a result of hydrodynamic physical damage or leukocyte attack¹⁶⁰. However, platelets can bind to and protect CTCs and improve their ability to establish secondary sites¹⁶¹. Platelet–CTC aggregates settled at distant sites can release cytokines that attract granulocytes¹⁶²; targeting platelets or granulocyte recruitment can prevent metastasis¹⁶². Additionally, abrogation of platelet–CTC binding, leading to a reduction in the number of circulating and potentially metastatic cells¹⁶³, might explain the suppression of metastasis by aspirin in breast and prostate cancer models¹⁶⁴. Survival and proliferation of newly deposited cancer cells in a metastatic site are arguably the most important stages of the metastatic process. Cancers with a propensity to metastasize do not grow in all organs, indicating that a limited number of organs provide a suitable stromal environment for their colonization. Preferred colonization sites, termed pre-metastatic niches, can be prepared in advance of the arrival of disseminated tumour cells through the actions of myeloid-derived suppressor cells (MDSCs) and tumour cell-derived extracellular vesicles (EVs), such as exosomes^17,165. Whether this process can provide novel therapeutic targets to limit the arrest and survival of metastatic cells remains unclear, with development of EV-specific drugs, for example, creating a challenge¹⁶⁶. Evidence also supports roles for neutrophils^167,168 and MDSCs¹⁶⁹ in metastatic colonization. Evasion of the antitumour immune response is another critical factor in metastatic colonization. No single tumour type seems to exhibit all these mechanisms; therefore, targeting any one stage of the metastatic process requires a tumour-specific understanding of the mechanisms involved.