HMGB1 in Radiotherapy: A Two Headed Signal Regulating Tumor Radiosensitivity and Immunity

Radiotherapy (RT) is a mainstay of cancer treatment. Recent studies have shown that RT not only directly induces cell death but also has late and sustained immune effects. High mobility group box 1 (HMGB1) is a nuclear protein released during RT, with location-dependent functions. It is essential for normal cellular function but also regulates the proliferation and migration of tumor cells by binding to high-affinity receptors. In this review, we summarize recent evidence on the functions of HMGB1 in RT according to the position, intracellular HMGB1 and extracellular HMGB1. Intracellular HMGB1 induces radiation tolerance in tumor cells by promoting DNA damage repair and autophagy. Extracellular HMGB1 plays a more intricate role in radiation-related immune responses, wherein it not only stimulates the anti-tumor immune response by facilitating the recognition of dying tumor cells but is also involved in maintaining immunosuppression. Factors that potentially affect the role of HMGB1 in RT-induced cytotoxicity have also been discussed in the context of possible therapeutic applications, which helps to develop effective and targeted radio-sensitization therapies.