Abstract Background: The most critical and life-threatening feature of malignant tumors is their ability to metastasize to distant organs, ultimately leading to patient mortality. Most metastases become clinically detectable only months or even years after the surgical removal of the primary tumor, indicating that they originate from tumor cells disseminated into the circulation and persisting in the body as minimal residual disease (MRD). It is widely assumed that the majority of circulating tumor cells (CTCs) rapidly disappear from the bloodstream following surgery, with a reported half-life of only a few hours. However, some of these cells clearly survive, either by recirculating or by entering protective niches within the body. Using the standardized maintrac® method, we demonstrated that substantial numbers of viable tumor cells can still be detected in peripheral blood several days after surgical intervention in patients with both lung and breast cancer. These findings strongly suggest that a fraction of CTCs is indeed capable of escaping rapid elimination. This raises an important question: why do most conventional CTC detection methods fail to identify these cells, both before and after surgery? How do tumor cells released into the bloodstream manage to remain undetected? Methods: Using fluorochrome- labeled anti-EpCAM antibody cells were dyed with the maintrac® approach right after blood draw and after resting the samples for up to 24 hours at room temperature on the shelf. At all times the presence of platelets was monitored using red fluorescing anti CD36 or anti-CD41/CD61 antibody. Results: Immediately after blood draw, no EpCAM-positive (green-fluorescing) CTCs were detectable. However, clusters of red-fluorescing platelets were observed, which, under transmitted light, were shown to be adherent to the circulating tumor cells. After 24 hours of resting at room temperature, a substantial number of viable EpCAM-positive tumor cells became detectable, with platelets visibly detached. Time-lapse imaging over 24 hours revealed progressive detachment of platelets from tumor cells, accompanied by increased anti-EpCAM staining intensity. These findings indicate that platelets form a cloak around circulating tumor cells in circulation, physically obstructing antibody binding and thereby preventing detection. Only upon platelet detachment could the tumor cells be reliably identified. Conclusion: Circulating tumor cells may evade detection by being cloaked in platelets. This platelet-mediated masking may not only hinder diagnostic detection but could also play a functional role in immune evasion and metastasis formation. Platelets expressing immune checkpoint molecules like PD-L1 may further suppress anti-tumor immune responses. These findings underscore the importance of considering platelet interactions in liquid biopsy techniques and highlight a potential target to improve cancer diagnostics and therapy. Citation Format: D. SchottM. PizonA. RiessK. Pachmann. The role of platelets in masking circulating tumor cells abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-03-08.
Schott et al. (Tue,) studied this question.