Bridging cancer cell-intrinsic driver genes and -extrinsic cell-cell communication with Driver2Comm.

Tumor development and progression are affected not only by cancer cell-intrinsic factors comprising complex genetic variations, but also by -extrinsic factors such as cell-cell communication (CCC)-mediated immunosuppression. However, whether and how these two types of factors influence each other remains an open question. We present Driver2Comm, a general computational framework designed to systematically identify intrinsic-extrinsic (IE) pathways that functionally connect cancer cell driver genes with their associated CCC signatures in the tumor microenvironment (TME). By applying Driver2Comm to single-cell and spatial transcriptomic datasets of multiple cancer types, we find that driver gene-associated CCC signatures play critical roles in immune regulation, metastasis, and therapy response. These signatures not only illuminate mechanisms of TME remodeling but also demonstrate clinical value in predicting patient survival and response to immune checkpoint blockade. Furthermore, Driver2Comm captures higher-order, cell-type-pair-specific CCC functional modules and spatially coherent CCC patterns in tissue contexts. As a generalizable tool, Driver2Comm bridges cancer genomics and cellular ecosystems, offering insights into biomarker discovery and combination therapy strategies.