Tumour immune microenvironment as the origin of heterotypic circulating tumour cell clusters and their impact on metastasis: An hypothesis

Abstract

Cancer metastasis remains a significant challenge in cancer treatment, contributing to most cancer-related deaths. Circulating Tumour Cells (CTCs) are crucial for the formation of metastases, and the presence of heterotypic CTC clusters has been associated with higher metastatic potential. We hypothesize that the tumour immune microenvironment (TIME) serves as a possible site for the origin of heterotypic CTC clusters. The interactions between CTCs and non-malignant cells within the TIME can promote cluster formation, facilitate intravasation, survival in the bloodstream, and successful extravasation at secondary sites. The survival of CTCs in circulation is limited due to immune attacks and shear stress; while the formation of heterotypic clusters provides a survival advantage to CTCs by evading immune recognition. Understanding the origin and survival mechanisms of these CTC clusters in the blood is crucial for developing strategies to prevent and treat metastatic cancer. The hypothesis highlights the role of the TIME in modulating CTC behaviour and suggests that targeting tumour-associated immune cells may help disrupt CTC clusters and potentially inhibit metastasis at its early stage.