Dualistic Roles of High Mobility Group Box 1 in Cancer and Inflammation

Background The High Mobility Group Box 1 (HMGB1) protein, a member of the HMG family, plays a crucial role in both cancer progression and inflammatory responses. HMGB1 can act as a damage‐associated molecular pattern (DAMP) to activate immune responses and modulate inflammation. Its dualistic roles in promoting and inhibiting tumor growth, as well as its involvement in DNA repair and drug resistance, make it a key target for understanding and treating cancer and inflammatory diseases. Objective This review aims to explore the dualistic roles of HMGB1 in cancer and inflammation, focusing on its pro‐inflammatory and anti‐inflammatory functions in the tumor microenvironment, its impact on DNA damage repair and tumor drug resistance, and its potential as a therapeutic target for cancer and inflammatory diseases. Methods We conducted a comprehensive review of the literature on HMGB1, analyzing its structural features, biological functions, and mechanisms of action in various pathological contexts. We also examined the impact of HMGB1 on tumor progression, immune responses, and metabolic reprogramming in cancer cells, as well as its role in inflammatory signaling pathways. Results HMGB1 exhibits both oncogenic and tumor‐suppressive effects in cancer. It promotes tumor growth, metastasis, and immune evasion through mechanisms such as shaping the tumor microenvironment, driving metabolic reprogramming, and inducing drug resistance. Conversely, HMGB1 can enhance anti‐tumor immunity by activating dendritic cells and T cells. In inflammation, HMGB1 acts as a DAMP, activating immune responses via receptors like RAGE and TLR4. Its redox state and subcellular localization determine its proinflammatory or anti‐inflammatory functions. Targeting HMGB1 has shown promise in preclinical and clinical studies, with potential applications in anti‐cancer and anti‐inflammatory therapies. Conclusion The dualistic roles of HMGB1 in cancer and inflammation highlight its complexity and potential as a therapeutic target. Future research should focus on elucidating the context‐specific mechanisms of HMGB1, developing precision‐targeted therapies to modulate its multifunctional activities, and translating these findings into clinical practice to improve patient outcomes.