Steroid receptor coactivators in immunity - From function to emerging translational opportunities

Steroid Receptor Coactivators (SRCs) comprise a family of three paralogous proteins. As transcriptional coactivators SRCs are essential for enabling the full transcriptional output of nuclear receptors (NRs). They regulate the transcriptional activity of nearly all NRs as well as a wide range of non-NR transcription factors. The central role of SRCs in gene regulation is reflected in their broad impact on major physiological and pathological processes, such as development, reproduction, metabolism, immunity and cancer. Although the major impact of SRCs on human health and disease established them as attractive therapeutic targets, their effective pharmacological targeting remained a challenge for nearly 2 decades after their discovery. The discovery of small-molecule modulators enabled the exploration of targeting SRCs in cancer but soon presented opportunities for broader therapeutic applications. The immunomodulatory effects observed upon SRC inhibition or stimulation were unexpected yet exciting, revealing new therapeutic potential that extends beyond cancer as a sole indication. In this review, we first provide an overview of the central roles of SRCs in normal physiology and cancer and outline the process that enabled the development of small molecules capable of modulating SRC activity. Finally, we present a comprehensive account on the functions of SRCs in immunity and discuss how their pharmacological targeting and genetic manipulation can reshape immune responses, enabling the development of new therapeutic strategies in cancer and beyond.