Bozkurt Emir, Kisakol Batuhan, Azimi Mohammadreza, Dussmann Heiko, Cho Sanghee, McDonough Elizabeth, Fay Joana, O'Grady Tony, Burke John P, McCawley Niamh, McNamara Deborah A, Longley Daniel B, Ginty Fiona, Prehn Jochen H M
Department of Physiology and Medical Physics & RCSI Centre for Systems Medicine, RCSI University of Medicine and Health Sciences, 123 St Stephen's Green, Dublin 2, Ireland.
Department of Mechanical Engineering, Virginia Tech, Blacksburg, VA, 24061, U.S.A.
bioRxiv. 2025 Jul 18:2025.07.15.662825. doi: 10.1101/2025.07.15.662825.
Cell-in-cell (CIC) structures, in which one cell is entirely engulfed by another, have been associated with poor outcomes in cancers. However, the mechanisms underlying this association remain poorly understood. We performed multiplex imaging of 56 cell identity, cell 'state' and cancer 'hallmark' proteins to characterise CICs, map their spatial interactions, and assess clinical associations across 444 tumour cores from 148 colorectal cancer patients, which contained over one million spatially resolved cells. We found that tumour regions containing CICs were associated with lower levels of cytotoxic T cells. We identified upregulated glucose metabolism as a consistent metabolic hallmark of CICs independent of cell type. Spatial analyses revealed that T cells adjacent to CICs underwent selective remodeling with distinct apoptotic and metabolic signatures. Finally, the presence of T cells within CIC neighbourhoods identified a subset of patients with improved survival. Our findings suggest that CICs may be a feature of metabolically competitive niches and a potential factor contributing to T-cell exclusion in tumours.
细胞内细胞（CIC）结构是指一个细胞被另一个细胞完全吞噬，这种结构与癌症的不良预后相关。然而，这种关联背后的机制仍知之甚少。我们对56种细胞身份、细胞“状态”和癌症“特征”蛋白进行了多重成像，以表征CIC，绘制它们的空间相互作用图谱，并评估来自148名结直肠癌患者的444个肿瘤核心的临床关联，这些肿瘤核心包含超过100万个空间分辨细胞。我们发现，含有CIC的肿瘤区域与细胞毒性T细胞水平较低有关。我们确定葡萄糖代谢上调是CIC一致的代谢特征，与细胞类型无关。空间分析显示，与CIC相邻的T细胞经历了具有不同凋亡和代谢特征的选择性重塑。最后，CIC邻域内T细胞的存在确定了一部分生存改善的患者。我们的研究结果表明，CIC可能是代谢竞争微环境的一个特征，也是导致肿瘤中T细胞排除的一个潜在因素。
