Dynamic molecular networks unveil the mechanism behind hypoxia‐induced tumour cell dormancy

ABSTRACT

Tumour cell dormancy is a reversible, non‐proliferative state in which cancer cells arrest in the G0 phase of the cell cycle. Increasingly recognized as a critical survival strategy, dormancy enables cancer cells to withstand therapeutic insult, escape immune surveillance, and endure hostile microenvironments. Clinically, dormant cells underlie extended asymptomatic intervals following primary treatment and are notably implicated in estrogen receptor‐positive (ER ⁺ ) breast cancer, prostate cancer, and clear cell renal cell carcinoma. In this review, we synthesize recent insights into hypoxia‐mediated dormancy and, using breast cancer bone metastasis as an archetypal model, delineate how spatiotemporally heterogeneous hypoxia shapes the metastatic cascade. Specifically, we show that graded hypoxia in the primary tumour initiates dormancy traits, while persistent hypoxia within metastatic niches – such as the bone marrow – reinforces and deepens quiescence. These transitions are orchestrated by stage‐specific activation of hypoxia‐inducible factor 1α (HIF‐1α) and its dynamic transcriptional outputs. We further argue that a mechanistic understanding of dormancy requires integrative frameworks that bridge single‐cell level regulatory programs – including cell‐cycle arrest, translational inhibition, and metabolic reprogramming – with systems‐level networks capturing the dynamic, multistage nature of metastasis. Such integration may uncover actionable vulnerabilities within dormant cell populations and guide the development of precision therapies targeting minimal residual disease.