Translational research aims to convert scientific discovery into tangible health improvements. At TRON, we employ single-cell RNA-sequencing (scRNA-seq) analysis to understand molecular mechanisms that could be leveraged to develop novel immunotherapeutic treatments in cancer and other severe diseases. Natural killer (NK) cells play a crucial role in cancer immunosurveillance, yet their cytotoxic function is frequently impaired within the tumor microenvironment (TME) through mechanisms that remain incompletely understood. Here, we constructed a comprehensive pan-cancer single-cell atlas to systematically investigate tumor-NK cell crosstalk contributing to NK cell dysfunction. For this purpose, more than one million cells from 130 patients across 13 solid tumor were integrated and harmonized across tissues and platforms. Automated cell type annotation combined with reference mapping resolved the transcriptional heterogeneity of NK subsets within the TME. Compared to blood-derived NK cells, we identified tumor-enriched NK populations, highlighting TME-induced transcriptional NK states. Cell-cell communication analysis further delineated receptor-ligand pairs mediating tumor-NK interactions which are functionally tested in vitro to confirm their role in tumor-driven NK cell exhaustion and tissue adaptation. Together, our results demonstrate how large-scale single-cell atlases can be employed to identify cell-cell communication axes that are relevant and targetable in disease.

Co-authors: Sophie-Christin Linkenbach, Aniello Federico, Nadia Correia, Tommaso Torcellan, Ayline Kuebler, Laura Kolb