ABSTRACT Superoxide dismutase 2 (SOD2) has been implicated in head and neck squamous cell carcinoma (HNSCC), yet its mechanistic contribution in regulating tumor responses to tyrosine kinase inhibitors (TKIs) remains unclear. Here, we investigated whether SOD2 shapes TKI sensitivity in HNSCC through a mitochondrial superoxide‐mitophagy axis. Bioinformatic analyses revealed that elevated SOD2 expression was negatively correlated with mitophagy signatures in HNSCC. Functional experiments showed that SOD2 silencing led to mitochondrial superoxide accumulation, impaired mitochondrial function, and significant mitophagy activation in HNSCC cells. Pharmacological modulation further supported a superoxide‐dependent mechanism, as Mito‐TEMPO suppressed mitochondrial superoxide and mitophagy induction, whereas rotenone enhanced mitochondrial superoxide and mitophagy activity. Importantly, SOD2 knockdown increased apoptotic susceptibility and sensitized HNSCC cells to TKI treatment, which was partially reversed by superoxide scavenging but reinforced by superoxide elevation. Consistently, SOD2 knockout xenograft models exhibited enhanced antitumor responsiveness to TKIs in vivo. Collectively, these findings identified SOD2 as a key regulator of mitochondrial redox homeostasis and mitophagy, thereby modulating therapeutic sensitivity in HNSCC, and suggest that targeting the SOD2‐superoxide metabolic axis may represent a promising strategy to improve TKIs efficacy in HNSCC.
Zhou et al. (Mon,) studied this question.