Enhancer of zeste homolog 2 (EZH2), a methyltransferase subunit of the polycomb repressive complex 2 (PRC2) that catalyzes histone H3 methylation on lysine 27 (H3K27), represents another epigenetic target to circumvent ICI resistance in HNSCC [73,74]. The gene discussed is EZH2; the disease is head and neck squamous cell carcinoma.