SMYD3 and neoplasm: In this work, we show that, independently of its immunomodulatory effects, SMYD3 depletion decreases the proliferative and colony-forming capacity, delays the G1 to S phase transition, decreases the invasive potential of HPV-negative HNSCC cells in vitro, and significantly attenuates tumor growth in vivo in immunocompromised HPV-negative HNSCC mouse models (Fig. 6).