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

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 across transcriptomic profiles from 19 tumor types, we reveal a recurrent downregulation of multiple ICT families—particularly ion channels—accompanied by selective upregulation of specific pump classes. Paired Clinical Proteomic Tumor Analysis Consortium transcriptomic-proteomic datasets further support this signature, showing that transportome tumor-normal transcript changes are largely preserved at the protein level, with high directional concordance. We interpret this pattern as a molecular signature of cancer-associated dedifferentiation and sensory signal decoupling, pointing toward a broader and underappreciated strategy by which tumors reconfigure their transmembrane communication interfaces to favor autonomy, immune evasion, and metabolic adaptation. Our findings uncover a widely conserved transportome reprogramming and provide a quantitative framework for future integrative studies of ICT function and their roles in cancer systems biology. NEW & NOTEWORTHY We provide a novel computational framework for transportome analysis. By applying it to transcriptomics and proteomics large public datasets, we found a striking and previously unrecognized pattern whereby ion channel families are consistently downregulated, whereas most transporter families are either preserved or upregulated. This functional asymmetry suggests a widespread suppression of channel-mediated signaling processes as a general strategy by which tumors reconfigure their transmembrane communication interfaces to favor dedifferentiation, autonomy, immune evasion, and metabolic adaptation.