Cellular Proliferation and Reprogramming in Pre‐Metastatic Niches: Mechanisms and Therapeutic Vulnerabilities

Cancer metastasis, the leading cause of cancer-related mortality, fundamentally depends on the proactive remodelling of distant organ microenvironments by primary tumours through systemic signals, creating a pre-metastatic niche before tumour cell arrival. This review systematically deconstructs the dynamic spatiotemporal evolution of the pre-metastatic niche, highlighting the multi-layered reprogramming of stromal, endothelial and immune cells that collectively cultivate a pro-tumourigenic and immunosuppressive microenvironment. We elucidate the biomechanical and biochemical sensing mechanisms, derived primarily from experimental models, that dictate the fate of disseminated tumour cells, governing the critical balance between dormancy maintenance and proliferative reactivation. Furthermore, we synthesize mechanistic insights alongside human tissue and liquid-biopsy correlative evidence on how metabolic resetting and epigenetic memory may contribute to sustaining pre-metastatic niche stability, and discuss how cutting-edge single-cell and spatial omics technologies are deciphering the intricate multicellular topological architecture of the niche. Ultimately, by mapping these complex systemic interactions across preclinical, biomarker and translational levels, we identify potential therapeutic vulnerabilities and advocate for a paradigm shift toward microenvironment normalization. While clinical validation remains an evolving frontier, targeting pre-metastatic niche priming represents a promising window that warrants rigorous clinical evaluation to intercept nascent metastasis before clinically detectable colonization occurs.