IRF4 in multiple myeloma: From molecular mechanisms to therapeutic targeting.

Interferon regulatory factor 4 (IRF4) is a lineage-restricted transcription factor essential for plasma cell differentiation and represents an important dependency in multiple myeloma (MM). Unlike other IRF family members, IRF4 is primarily induced by antigen receptor signaling rather than interferon stimulation, linking B-cell development, plasma cell biology, and MM pathogenesis. In MM, IRF4 expression and activity are regulated by multilayered genetic, epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms, collectively maintaining IRF4-centered transcriptional programs that support malignant plasma cell identity and survival. Functionally, IRF4 regulates transcriptional networks controlling myeloma cell proliferation, stress adaptation, and survival, while emerging evidence indicates that IRF4 may also have context-dependent roles in immune regulation. The dependency of malignant plasma cells on IRF4 provides a rationale for therapeutic targeting, and multiple strategies have been developed to modulate IRF4 expression or activity. This review provides an integrated overview of IRF4 regulation and function in MM, highlighting its role in disease pathogenesis, therapeutic strategies, translational challenges, and future opportunities for precision targeting.