Tumor Microemboli, Dormancy, and Premetastatic Niches as Three Mechanisms of Metastasis: Which to Target? And When?

Metastasis is a complex process driven by multiple, incompletely understood mechanisms that enable disseminated tumor cells (DTCs) to colonize distant organs.It remains the leading cause of cancer-related death, yet definitive preventive strategies are still lacking.In this narrative review, we focus on three major mechanisms of metastasis: tumor microemboli, tumor cell dormancy, and premetastatic niche (PMN) formation.These mechanisms represent critical hallmarks associated with a high probability of successful metastasis.Hypothetically, when targeting one of these mechanisms, ensuring the absence or therapeutic control of the other two appears necessary if the goal is to suppress metastasis rather than merely block a single pathway.We discuss current and emerging therapeutics targeting each mechanism and propose a timing-and context-dependent framework to optimize their efficacy.We highlight that therapeutic targeting of tumor microemboli is most relevant for larger heterotypic clusters, whereas smaller clusters may rely on alternative mechanisms for successful metastasis.PMN formation follows a sequential cascade of tumor-derived and host tissue signals.This sequence makes the timing of intervention critical, such that the same agent may be effective at an early stage but lose efficacy later.For tumor dormancy, we distinguish between the timeframes before and after the establishment of dormant DTCs, and we review the therapeutics accordingly.We further propose that dormancy is a dynamic state characterized by cycles of awakening and rapid re-entry into quiescence, comparable to herpes simplex virus reactivation and dormancy.This timely re-entry into dormancy would be conditioned by the presence in situ of an interferon-gamma (IFN-γ)-secreting T-cell pool.Dormancy is also expected to serve as a lastresort mechanism of metastasis in a given tissue when efficient multicellular microemboli and a PMN are absent at that site.The rationale for this consideration is based on differences in metastatic efficiency.Multicellular microemboli and an established PMN possess a higher and more immediate capacity to generate metastases than DTCs that enter dormancy and only later reawaken under favorable conditions.Consequently, ensuring the absence or the suppression of these mechanisms appears necessary before targeting tumor dormancy.This timing-oriented perspective aims to shift the focus from treating established metastases toward the rational prevention of metastatic colonization.