Cell engulfment defines spatially distinct competitive metabolic niches associated with clinical outcomes in colorectal cancer.

Cell competition is an emerging mechanism in which mammalian tissues maintain homeostasis by eliminating less fit (loser) cells through direct interactions with fitter (winner) neighbouring cells. In cancer, these competitive interactions may drive tumour evolution; however, spatial organisation and clinical relevance of these events remain poorly understood. One mechanism by which winner cells eliminate loser cells is engulfment, resulting in cell-in-cell (CIC) formation. Although CICs have been observed in many tumour types for over a century, their cellular composition, spatial context, interactions with the tumour microenvironment, and biological significance in human cancers remain unclear. Here, we systematically characterised the cellular identity and functional states of CICs in situ, examined their spatial interactions within the tumour microenvironment, and assessed their clinical relevance using spatially resolved single-cell data from a large cohort of colorectal cancer patients. We demonstrated that CICs occurred predominantly between cancer cells but also involved cancer stem cell (CSC)-like populations and cytotoxic T cells. Engulfed (inner) cancer and CSC-like cells displayed molecular features consistent with a loser-cell phenotype, including increased apoptosis and reduced proliferation, whereas outer cancer cells exhibited winner-cell features such as upregulated glycolysis. Live-cell time-lapse experiments demonstrated that glucose accumulated in inner cells during lysosomal degradation following cell engulfment. Spatial analysis further revealed distinct CIC neighbourhoods, which we defined based on proximity to engulfment events. Cells within these regions, particularly CSC-like cells and cytotoxic T cells, exhibited increased metabolic stress, suggesting local competition for nutrients. Importantly, the presence of cytotoxic T cells within CIC neighbourhoods and spatial co-occurrence between cancer cells and CSC-like populations were associated with improved patient outcomes. Together, our findings demonstrate that cell engulfment defines spatially organised competitive niches and may reflect cell competition within complex tumour microenvironments.