Table 2.

Current and future strategies to overcome hypoxia induced radioresistance in HNSCC.

Target Strategy	Comments	References
DDR	Alterations in the DDR in hypoxic tumour cells have been observed, so DDR could be a suitable target. For example, ATR, DNA-PKcs and PARP inhibitors should be explored more in hypoxic HNSCC models.	[84,85,86,87,88,89,90]
HIF	HIF overexpression linked to poor prognosis of HNSCC, so remains an attractive target. Limited reported evidence on the impact of HIF inhibition on HNSCC radioresistance.	[91,92,93,94,95]
Immunotherapy	Association between PDL-1 and HIF-1α, and that hypoxia may alter tumour immunosurveillance. Possibility for targeting both HIF-1α and PDL-1 to overcome hypoxic radioresistance. Clinical trials in HNSCC combining immunotherapy with radiotherapy are ongoing.	[96,97,98,99,100]
High LET and FLASH radiotherapy	High-LET radiotherapy reduces the need for oxygen within the tumour for effectiveness, so has the potential to overcome hypoxic radioresistance. However, evidence of high-LET and FLASH radiotherapy in HNSCC is lacking.	[101,102,103,104,105,106,107]