The Role of Hypoxia-Inducible Factors (HIFs) in Triple-Negative Breast Cancer Radiation Resistance

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking estrogen receptor, progesterone receptor, and HER2 expression. Although ionizing radiation (IR) is widely used to treat TNBC, tumour radioresistance remains a major therapeutic barrier. Tumour hypoxia contributes to resistance by limiting IR-induced reactive oxygen species generation and activating pathways that promote tumour survival, progression, and aggressiveness. Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcription factors that regulate many of these pathways; however, the mechanisms underlying HIF-mediated radioresistance in TNBC remain incompletely characterized. This review examines the role of HIF signalling in TNBC radiation resistance and emerging strategies for overcoming hypoxia-mediated radioresistance. PubMed and Web of Science were searched for studies investigating HIFs, TNBC, and radiation response. Relevant studies were screened against the eligibility criteria and analyzed for mechanistic findings and therapeutic interventions targeting HIF-associated pathways. The literature indicates that HIF activation promotes radioresistance through multiple mechanisms, including altered ferroptosis and pH regulation. Proposed countermeasures include pharmacologic inhibition of HIF signalling, nanotechnology-based delivery systems, and alternative radiation-based modalities, including photodynamic and radiodynamic therapies. Collectively, these findings identify HIF signalling as a central mediator of TNBC radioresistance and a promising therapeutic target for improving radiotherapy outcomes.