Cancer cells can be conceived as “living organisms” interacting with cellular or non‐cellular components in the host internal environment, not only the local tumor microenvironment but also the distant organ niches, as well as the immune, nervous and endocrine systems, to construct a self‐sustainable tumor ecosystem. With increasing evidence for the systemic tumor‐host interplay, we predict that a new era of cancer therapy targeting the ecosystemic vulnerability of human malignancies has come. Revolving around the tumor ecosystem scoped as different hierarchies of primary, regional, distal and systemic onco‐spheres, we comprehensively review the tumor‐host interaction among cancer cells and their local microenvironment, distant organ niches, immune, nervous and endocrine systems, highlighting material and energy flow with tumor ecological homeostasis as an internal driving force. We also substantiate the knowledge of visualizing, modelling and subtyping this dynamically intertwined network with recent technological advances, and discuss ecologically rational strategies for more effective cancer therapies.
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