HMGB1 as Double-Edged Regulator of Cancer Therapy: Mechanistic Roles in Chemotherapy Resistance and Immunotherapy Response

Abstract: High-mobility group box 1 (HMGB1) is a ubiquitous non-histone nuclear protein with multifaceted roles in cancer biology. Emerging evidence suggests that the biological effects of HMGB1 are highly context-dependent, being determined by its subcellular localization, redox state, and release kinetics. Nuclear HMGB1 regulates chromatin structure and genome stability, whereas cytoplasmic HMGB1 controls autophagy and cell survival. When released extracellularly during cellular stress or therapy-induced immunogenic cell death, HMGB1 functions as a damage-associated molecular pattern that activates innate and adaptive immunity through pattern-recognition receptors such as Toll-like receptor 4. In this narrative review, we synthesize recent mechanistic and translational studies to clarify how HMGB1 regulates tumor proliferation, metastasis, and therapeutic responses under different treatment modalities. We particularly discuss the dual roles of HMGB1 in chemotherapy and emerging immunotherapies. Collectively, these insights highlight HMGB1 as a potential biomarker of treatment response and a therapeutically modifiable node for optimizing chemo-immunotherapy combination strategies. Keywords: HMGB1, cancer, treatment, chemotherapy, immunotherapy