Mechanisms of Cancer Metastasis: Dormancy, Immune Evasion, Pre-Metastatic Niches, and Emerging Therapeutic Strategies

Metastatic relapse often reflects the survival of a small population of disseminated tumor cells (DTCs) that take up residence in distant organs and then shift into a dormant state. Rather than dividing, these cells sit quietly for long periods and rely on local niche signals to stay inactive and avoid therapy. Dormant cells are difficult to eliminate because the immune system cannot detect them, and treatments aimed at actively growing cells are ineffective. DTCs stop oncogenic signaling and start stress-response and cell-cycle arrest pathways. These pathways are often characterized by higher levels of cyclin-dependent kinase (CDK) inhibitors and greater p38 signaling than ERK signaling. LIFR–STAT3 signaling in the bone marrow supports quiescence in breast cancer cells, while inflammatory cytokines and Wnt/BMP antagonists in the lung microenvironment can trigger reactivation of cancer DTCs. Because these dormant DTCs are not cycling, standard cytotoxic agents rarely remove them. Current strategies are now testing immune-directed therapies. Recent single-cell and long-read sequencing efforts have started to reveal the transcriptional programs that mark DTCs, including stress-response and quiescence signatures that differ from the primary tumor. These insights are shaping therapies for interrupting dormancy and lowering the risk of late metastatic relapse.