Circulating tumor cell-immune cell clusters: dynamic engines of metastasis.

Abstract

Circulating tumor cell (CTC) clusters are potent drivers of metastasis, exhibiting markedly greater metastatic capacity than single CTCs. Beyond homotypic CTC clusters, CTCs dynamically engage immune cells to form heterotypic clusters with enhanced metastatic fitness. Rather than passive assemblies, these clusters function as coordinated metastatic ecosystems, integrating adhesion, immune modulation, and metabolic adaptation to promote survival, plasticity, and immune evasion. Recent advances in CTC isolation, single-cell and spatial multiomics, and artificial intelligence-driven analyses have enabled unprecedented resolution of these dynamic interactions. Together, these findings support a conceptual shift from isolated single-cell dissemination to multicellular cooperation as an important principle of metastasis and identify CTC-immune cell clusters as actionable targets for next-generation therapies to boost immunity and prevent metastasis.