MTDH and head and neck squamous cell carcinoma: E2F4 was initially identified as a transcriptional repressor;77 however, accumulating evidence suggests that E2F4 also promotes gene transcription.50,78–80 Moreover, E2F4 was found to promote cancer progression,81 and more importantly, the expression of E2F4 was negatively correlated with CD8+ T-cell infiltration in head and neck squamous cell carcinoma and hepatocellular carcinoma.82,83 Consistent with these findings, we demonstrated that E2F4 transcriptionally activated MTDH, thereby increasing its expression (Fig. 5 and Supplementary Fig. 9).