HMGB1 in exosomes derived from gastric cancer cells induces M2‐like macrophage polarization by inhibiting the NF‐κB signaling pathway

Abstract Gastric cancer (GC) seriously threatens human health. High mobility group protein B1 (HMGB1) and M2‐like macrophages are closely associated with core events about human cancers, such as invasion, and metastasis, and cancer microenvironment. This study mainly determined the regulatory effect of HMGB1 in GC cell‐derived exosomes on M2‐like macrophage polarization as well as the underlying mechanism. HMGB1 was found to be highly expressed in gastric tissue specimens, which might lead to the poor prognosis of GC. High levels of HMGB1 were also observed in the plasma of GC patients, indicating the possibility that it regulates the immune microenvironment via exosomes. Further study revealed and confirmed the regulatory effect of exosomes derived from GC cells with high HMGB1 level on inducing M2‐like macrophage polarization. Mechanistically, by interacting with the transcription factor POU2F1, exosomal HMGB1 inhibited the transcriptional activity of p50, resulting in the inactivation of NF‐κB signaling pathway and thereby inducing M2‐like macrophage polarization. Moreover, instead of promoting the proliferation of GC cells, exosomes with high HMGB1 levels induced M2‐like macrophage polarization and promoted GC progression. This study reveals a novel mechanism by which HMGB1 promotes GC progression, which may provide new insights for improving the efficacy of cancer immunotherapy.