As the chemotherapeutic activity of β-lap is intrinsically linked to the availability of NAD(P)H, and our prior dynamic flux balance analysis identified mitochondrial MTHFD2 as a key driver of NAD(P)H in HNSCC, including the SCC-61/rSCC-61 cells (20, 21), we sought to investigate here the contribution of MTHFD2 to the efficacy of response to β-lap when used alone or combined with ionizing radiation. Here, MTHFD2 is linked to head and neck squamous cell carcinoma.