Circulating Tumor Cells in the Blood Microenvironment: Survival Mechanisms and Metastatic Potential

Abstract Background Circulating tumor cells (CTCs) play a central role in cancer metastasis by acting as seeds for dissemination to distant organs. However, upon entering the bloodstream, CTCs encounter multiple lethal challenges, including shear stress, anoikis, and immune surveillance, resulting in the survival of only a small subset of cells. Understanding how CTCs overcome these hostile conditions is critical for elucidating the metastatic process and identifying potential therapeutic targets. Summary of Content Accumulating evidence indicates that CTCs exhibit remarkable phenotypic plasticity and heterogeneity, enabling dynamic transitions along the epithelial–mesenchymal spectrum. In addition, CTCs can form multicellular clusters and interact with various blood components, which may enhance their survival and metastatic potential. Emerging studies also suggest that CTCs can acquire features resembling stem cells and immune cells, contributing to immune evasion and adaptability within the circulation. In this review, we discuss the key biological characteristics of CTCs and the adaptive strategies that support their persistence in the bloodstream, including plasticity, clustering, and interactions with the blood microenvironment. Conclusion CTCs represent a highly adaptable and heterogeneous population that utilizes multiple survival strategies to persist in the bloodstream and contribute to metastasis. A deeper molecular exploration is required to identify the specific genes that govern critical adaptive traits, particularly those mediating cell clustering, anoikis resistance and immune evasion. Understanding of these mechanisms may provide insights into novel therapeutic approaches aimed at preventing metastatic progression, particularly in early dissemination or minimal residual disease settings. Graphical Abstract The metastatic cascade. The metastatic cascade is a multistep biological process through which cancer cells disseminate from a primary tumor to distant organs, ultimately forming secondary tumors. (1) EMT is activated, allowing cancer cells to lose intercellular adhesion and invade surrounding tissues by degrading the ECM via proteolytic enzymes such as matrix MMPs. (2) Individual tumor cells or multicellular clusters then enter the blood or lymphatic vessels in a process known as intravasation. Once in the circulation, these CTCs are exposed to hostile conditions, including mechanical shear stress, immune surveillance, and anchorage-independent stress (anoikis). (3) Surviving CTCs subsequently exit the bloodstream at distant sites through extravasation. (4) After colonizing a new tissue microenvironment, disseminated cancer cells must adapt and survive to establish micrometastases, which may eventually progress to clinically detectable macrometastases. Created with BioRender.com.