Fig. 6.

Implications of hypoxia-linked alterations in HPV-positive cancer cells. Hypoxia results in E6/E7 repression and inhibition of cellular proliferation of HPV-positive cancer cells. The concomitant interference with mTOR signaling by hypoxia allows the cells to evade senescence. The growth inhibition under hypoxia contributes to the resistance of HPV-positive cancer cells toward CT. The ability of hypoxic HPV-positive cancer cells to block E6/E7 expression without undergoing senescence also provides therapeutic resistance toward strategies aiming at E6/E7 inhibition. The repression of E6/E7 antigen synthesis, together with the immunosuppressive effects of hypoxia, support evasion of hypoxic HPV-positive cancer cells from the host’s immune response and protects against immunotherapeutic approaches targeting E6/E7. Owing to the reversibility of hypoxia-linked growth inhibition, dormant hypoxic HPV-positive cells could serve as a reservoir for tumor recurrence on reoxygenation.