DDX3 as a post-transcriptional hub coordinating immune evasion, mitochondrial plasticity, and cancer progression.

DEAD-box RNA helicase 3 (DDX3) is a key regulator of RNA metabolism whose role in cancer extends beyond canonical RNA unwinding and translational control. Emerging evidence indicates that DDX3 functions as a context-dependent post-transcriptional integrator coordinating adaptive programs essential for malignant progression. Rather than acting as a classical oncogene or tumor suppressor, DDX3 shapes cancer phenotypes by synchronizing immune regulation and mitochondrial plasticity at the RNA level. This review summarizes recent mechanistic and translational studies illustrating how DDX3 orchestrates tumor immune evasion, metabolic adaptation, and therapy resistance through post-transcriptional regulation. We highlight DDX3-mediated modulation of immune signaling and immune checkpoint dynamics, particularly its 3' untranslated region-dependent control of PD-L1 cell-surface presentation, which critically influences tumor immune surveillance and responsiveness to immunotherapy. In parallel, we discuss how DDX3 governs mitochondrial homeostasis, dynamics, and bioenergetic flexibility by selectively regulating stress-responsive transcripts, enabling cancer cells to withstand metabolic and oxidative stress. We further propose an integrative framework in which immune escape and mitochondrial plasticity are coordinately regulated by DDX3-centered RNA regulatory networks. This model reconciles the context-dependent roles of DDX3 across cancer types and disease stages and highlights DDX3 as a systems-level regulator and a potential target for precision combination therapies.