Mapping the functional dark proteome in cancer

A generation after the genomics revolution, and with the advent of proteomic technologies, the dark proteome now stands as a potential new direction for cancer science and therapeutics. The dark proteome covers a vast terrain of previously undiscovered and uncharacterized protein molecules derived from alternative genomic loci or altered RNA translation. Over the past decade, an unprecedented depth of resolution of the dark proteome has been attained, identifying diverse classes of dark proteins with thousands of members each. Increasingly, individual dark proteins are also being characterized as functional components of cancer cell biology as well as potential therapeutic targets. Therefore, as a whole, the dark proteome offers the possibility to advance cancer science, diagnosis and treatment. Yet, many fundamental questions about the dark proteome remain, including key gaps in knowledge regarding its regulation, contribution to cancer phenotypes and antigenicity, and tractability for clinical-grade therapies. This Perspective outlines the current state of knowledge of the dark proteome in cancer, highlighting critical areas in which further research is needed. Furthermore, it poses guiding questions that illuminate important directions of growth for the field of the cancer dark proteome.