According to the 2018 Global Cancer Statistics (Bray et al., 2018), colorectal cancer (CRC) constitutes approximately 10 % of all incident cancer cases and mortality worldwide. Globally, colorectal cancer ranks as the second-leading cancer in women and the third-leading in men (Dekker et al., 2019). At initial diagnosis, approximately 20 % of patients with colorectal cancer present stage IV disease, characterized by distant metastasis (Ni et al., 2023). Tumor dormancy represents a critical phase in metastatic progression, during which disseminated cancer cells remain quiescent within distant organs without the formation of clinically detectable tumors. Although a consensus definition remains elusive, tumor dormancy is widely regarded as a dynamic equilibrium between tumor cell proliferation and apoptosis, maintaining a balance where cellular expansion is offset by cell death (Endo and Inoue, 2019, Hedley and Chambers, 2009, Omokehinde and Johnson, 2021).

Recent advances in CRC research have driven treatment strategies toward multi-target and multidimensional therapeutic paradigms(Niu et al., 2022). At the molecular level, dysregulation of miR-494 and SPHK1 downregulation modulate tumor dormancy through metabolic reprogramming, whereas the SHP-2/Ang-Tie2 pathway and EVA1B-mediated recruitment of MDSCs collectively foster an immunosuppressive tumor microenvironment (Jia et al., 2024, Wu et al., 2023, Wu et al., 2020, Xia et al., 2024). Current therapeutic approaches are expanding to include miRNA targeting, metabolic enzyme inhibition, immune microenvironment modulation, and anti-angiogenic agents in combination regimens (Cao et al., 2025, Jia et al., 2024, Li and Qiao, 2022, Liu et al., 2024, Wu et al., 2023, Wu et al., 2020, Xia et al., 2024). Notably, the integration of mindfulness therapy underscores the growing recognition of biopsychosocial models in oncology (Feng et al., 2024). Collectively, these discoveries establish a framework for precision medicine grounded in multidimensional manipulation of the tumor microenvironment.

Consequently, elucidating the molecular mechanisms underlying dormancy maintenance and reactivation of tumor cells in CRC is critical for developing targeted effective treatment strategies (Gomatou et al., 2021). This review systematically examines: (1) the biological hallmarks of metastatic tumor dormancy in CRC, encompassing distinctive molecular markers and functional phenotypes of dormant tumor cells; (2) key regulatory mechanisms of tumor dormancy, focusing on cell cycle control proteins, critical signaling pathways, cytokine networks, and extracellular matrix remodeling in the tumor microenvironment; (3) emerging therapeutic strategies targeting these mechanisms, with particular emphasis on molecular-targeted agents, immunomodulatory approaches and rational combination therapies. Collectively, this synthesis aims to advance therapeutic paradigms for colorectal cancer by translating mechanistic insights into clinically actionable strategies to improve patient outcomes.