According to the alterations of the subcellular locations, receptors, and expression levels, HMGB1 is associated with the hallmarks of cancer proposed by Hanahan and Weinberg [
12]. HMGB1 appears to play paradoxical roles during the development and therapy of cancer. On the one hand, HMGB1 can contribute to tumorigenesis. Excessive HMGB1 production caused by chronic inflammatory response seems to be associated with tumorigenesis. For example, by combining with RAGE, HMGB1 plays an important role in regulating oval cells activation and inflammation-associated liver carcinogenesis in mice [
13]. In established cancers, HMGB1 produced by tumor cells may exacerbate inflammation-related immunosuppression. For instance, previous research indicated that LPS induced the release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in a HMGB1-dependent manner to improve colon cancer progression [
14]. However, the underlying mechanism of HMGB1 in the transformation of inflammation and cancer needs to be further studied. It has been reported that HMGB1 can be released to extracellular context by necrotic cells under hypoxia in growing solid tumor. Extracellular HMGB1 promotes the release of cytokines such as IL-6 and IL-8 by activating MAPK- and MyD88-dependent NF-κB pathways, which in turn stimulates tumor cells proliferation, angiogenesis, EMT, invasion, and metastasis. Nucleus and cytoplasmic HMGB1 promotes autophagy and inhibits apoptosis of tumor cells to induce chemotherapy resistance [
15]. On the other hand, HMGB1 plays a protective role in the suppression of tumor and tumor chemoradiotherapy and immunotherapy. Nucleus HMGB1 assists in the regulation of telomere and maintenance of genome stability. Loss of HMGB1 results in the instability of genome and leads to tumorigenesis. Thus, the roles of HMGB1 in regulation of DNA damage repair and cancer etiology indicate that targeting chromosomal architectural HMGB1 may provide a new perspective for cancer therapy [
16]. HMGB1 located in the cytosol or mitochondria may bind to autophagy associated genes like Beclin 1 to regulate cell autophagy and mitophagy. Absence of HMGB1 results in autophagy deficiency and increased apoptosis, leading to tumorigenesis. Intracellular HMGB1 functions as a tumor suppressor by binding tumor suppressor proteins like Rb. But it remains to be studied whether HMGB1 interacts with other tumor suppressors or oncoproteins. Extracellular HMGB1 enhances chemotherapy efficacy by transforming tumor cells from apoptosis to senescence [
15]. In addition, HMGB1 can mediate immunogenic cell death during chemoradiotherapy and enhance anti-tumor immunity. In response to chemotherapy like anthracycline or radiotherapy, HMGB1 can be rapidly released from dead cells as an alarming molecule. Upon release from necrotic cells or secreted by activated macrophages, HMGB1 can recruit inflammatory cells and mediate interactions between NK cells, dendritic cells (DCs), and macrophages. Activated NK cells provide an additional source of HMGB1, which is released into the immunological synapse between NK cells and immature DCs, promoting the maturation of DCs and the induction of Th1 response [
17]. In addition, HMGB1 produced from NSCLC cells induced by docetaxel can stimulate T cells for anti-tumor immune response and improve immunotherapy effects like CAR-T cells [
5]. Therefore, modulating HMGB1 may provide a potential combination strategy for cancer chemoradiotherapy and immunotherapy.