The pervasive negative regulation of ion channel functional families across human cancers

Abstract The transmembrane transport of molecules and ions is fundamental to cellular homeostasis and coordination of physiological processes. During tumorigenesis, these processes undergo significant alterations in response to oncogenic transformations and microenvironmental pressures. However, a comprehensive systems-level characterization of transportome alterations across cancer types has been lacking. Here, we integrate structural, functional, and mechanistic annotations of all known human Ion Channels and Transporters (ICTs) into a curated database, organizing them into biologically coherent gene sets based on shared physiological and biophysical properties such as permeant species, gating mechanism, and transport directionality. By leveraging Gene Set Enrichment Analysis (GSEA) across transcriptomic profiles from 19 tumor types, we reveal a recurrent downregulation of ICTs—particularly ion channels—accompanied by selective upregulation of specific pump classes. Our findings uncover a conserved signature of transportome reprogramming in cancer and provide a quantitative framework for future integrative studies of ICT function. This work highlights both the complexity and plasticity of cellular transport systems in oncogenesis and offers a resource for modeling their roles in cancer systems biology.