Metastasis on pause: How dormant tumor cells stay hidden within the tumor microenvironment and evade immune surveillance

Abstract

Metastasis remains the leading cause of cancer‐related mortality. Even after major advances in early detection and systemic therapies, long‐term disease recurrence frequently arises from the presence of dormant disseminated tumor cells (DTCs) at distant sites. Dormant DTCs disseminate from the primary tumor and reside in secondary organs in a reversible quiescent state characterized by minimal proliferation, enabling resistance to therapies that target actively dividing cells. Despite their inactivity, dormant DTCs are far from inert. Dormant DTCs dynamically interact with the surrounding tumor microenvironment (TME), including stromal, vascular, and immune components, to establish niches that maintain quiescence while limiting immune detection. While the mechanisms by which proliferating cancer cells evade immune surveillance have been extensively studied, the processes governing immune regulation, immune‐mediated dormancy, and immune evasion of dormant DTCs remain incompletely integrated across literature. In this review, we explore recent advances describing how microenvironmental cues and immune pressures converge on tumor cell–intrinsic programs to sustain dormancy, promote immune tolerance, and enable long‐term survival of DTCs across different organs and cancer types. We further discuss conditions that disrupt this equilibrium and drive escape from dormancy, as well as emerging therapeutic strategies aimed at eliminating or controlling dormant DTCs by targeting dormancy‐specific immune and microenvironmental interactions.