The Diverse Roles of the MEF2 Transcription Factor Family in Tumor Progression and Emerging Therapeutic Opportunities

The myocyte enhancer factor 2 (MEF2) transcription factor family plays crucial roles in differentiation, lineage specification, stress responses, and tissue homeostasis. Recent investigations have shown that the dysregulation of MEF2A, MEF2B, MEF2C, and MEF2D is associated with tumorigenesis, tumor progression, and adverse clinicopathological features in several cancers. MEF2B has a particularly important role in B-cell malignancies, where recurrent mutations deregulate BCL6 and promote lymphoma progression. MEF2A, MEF2C, and MEF2D also regulate malignant phenotypes, including proliferation, migration, invasion, apoptosis, drug resistance, angiogenesis, inflammation, and immune evasion, by the mechanism of regulating cell-cycle regulators, apoptosis-related genes, EMT-related genes, and other transcriptional programs. This review summarizes the mechanisms by which MEF2 family members contribute to tumor initiation and progression, with added emphasis on MEF2B mutations and MEF2D fusions. We also discuss clinical associations with overall survival and recurrence in solid tumors and hematologic malignancies. Because MEF2 proteins are transcription factors with broad physiological functions, we evaluate therapeutic strategies: RNA interference, genetic perturbation, small molecules that alter MEF2-dependent transcription, and PROTAC or oligonucleotide-PROTAC. These platforms remain promising but require MEF2-specific validation, tumor-selective delivery, and careful toxicity assessment.