Over the last four decades, the cancer biology field has concentrated on cellular and microenvironmental drivers of metastasis. Despite this focus, mortality rates upon diagnosis of metastatic disease remain essentially unchanged. Would a small change in perspective help? Knowing what constitutes an inhospitable, rather than hospitable, microenvironment could provide the inspiration necessary to develop better therapies and preventative strategies. In this review, we canvas the literature for hints about what characteristics four common antimetastatic niches—skeletal muscle, spleen, thyroid, and yellow bone marrow—have in common. We posit that thorough molecular and mechanistic characterization of antimetastatic tissues may inspire reimagined therapies that inhibit metastatic development and/or progression in an enduring manner.

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