Circulating tumor cells (CTCs) play a pivotal role in the metastatic process, acting as precursors to distant metastasis in cancer patients. Recent studies have highlighted the mechanisms by which CTCs evade immune surveillance. For instance, Yang et al. demonstrated that CTCs shielded with extracellular vesicle-derived CD45 can evade T cell attacks, facilitating metastasis (ref: Yang doi.org/10.1038/s41392-024-01789-1/). Furthermore, Xin et al. found that CTCs capable of surviving fluid shear stress during hematogenous dissemination possess metastasis-initiating competence, characterized by traits such as stemness and enhanced migration potential (ref: Xin doi.org/10.1016/j.canlet.2024.216870/). This suggests that the ability to withstand mechanical forces in the bloodstream is a critical factor in the metastatic cascade. In addition, García-Chamé et al. introduced a microfluidic platform that mimics the endothelial barrier, allowing for the study of CTC extravasation, revealing that the adhesion properties of CTCs are influenced by the type and density of adhesion peptides (ref: García-Chamé doi.org/10.1002/anie.202318805/). These findings collectively underscore the heterogeneity of CTCs and their adaptive mechanisms that facilitate metastasis, presenting potential therapeutic targets for intervention. Moreover, the genetic and phenotypic profiling of single living CTCs has emerged as a promising approach for predicting treatment efficacy. Dong et al. developed a nanoplatform for capturing CTCs and analyzing their response to immune checkpoint inhibitors, highlighting the importance of understanding individual CTC characteristics in tailoring immunotherapy (ref: Dong doi.org/10.1073/pnas.2315168121/). This integrative approach not only enhances our understanding of CTC biology but also paves the way for personalized cancer therapies. The studies collectively emphasize the need for advanced methodologies to dissect CTC behavior and their implications in cancer progression and treatment resistance.