CTC cluster in breast cancer: synergetic metastasis promotion mechanism and transformation path from platelet cloaking to leukocyte escort.

Circulating tumor cell (CTC) clusters are potent drivers of metastasis in breast cancer, and their survival and dissemination within the circulatory system are critically governed by dynamic interactions with the host microenvironment. Two key mechanisms-"platelet cloaking" and "leukocyte escort"-have emerged as central axes that amplify the metastatic potential of these clusters. This review synthesizes these parallel yet intersecting pathways, elucidates the biological basis for their synergistic interplay, and proposes a translational roadmap from mechanistic insight to clinical application. Accumulating evidence indicates that breast cancer CTC clusters originate from the oligoclonal shedding of primary tumor cells, with their structural integrity maintained by the intercellular adhesion molecule plakoglobin. Within the circulation, CTCs form heterogeneous clusters with neutrophils, a phenomenon strongly associated with poor patient prognosis that activates cell cycle programs, supporting the concept of "proliferation in transit". Concurrently, platelet cloaking, mediated by molecules such as P-selectin, confers multiple survival advantages: it shields clusters from hemodynamic shear stress, facilitates evasion of immune surveillance (notably NK cell-mediated cytotoxicity), and forms microthrombi that act as "docking scaffolds" to enhance extravasation efficiency. While the advent of low-shear microfluidic technologies now enables the precise isolation and functional characterization of these clusters, a significant gap persists in high-level clinical evidence for interventions. Preclinical studies have identified the selectin/integrin network and fibrinogen as highly promising therapeutic targets. Therefore, we propose the implementation of mechanism-driven, exploratory clinical trials guided by biomarkers (e.g., dynamic changes in CTC clusters) and conducted within the perioperative "window of opportunity" to validate the clinical feasibility and safety of therapeutically targeting this "platelet cloaking and leukocyte escort" axis in breast cancer.