HSP27/IL-6 axis promotes OSCC chemoresistance, invasion and migration by orchestrating macrophages via a positive feedback loop.

Novel strategies to disrupt tumor progression have emerged from studying the interactions between tumor cells and tumor-associated macrophages (TAMs). However, the molecular mechanisms of interactions between tumor cells and TAMs underlying oral squamous cell carcinoma (OSCC) progression have not been fully elucidated. This study explored the molecular mechanism of the HSP27/IL-6 axis in OSCC chemoresistance, invasion, and migration. Here, we demonstrated the higher expression of HSP27 in OSCC cells. Paracrine HSP27 from OSCC cells enhanced chemoresistance, invasion, migration, and EMT in OSCC by inducing M2 polarization and IL-6 secretion in TAMs. HSP27 and IL-6 established a positive feedback loop between OSCC cells and M2 TAMs. TAMs-derived IL-6 orchestrated OSCC stemness and chemoresistance through upregulating β-catenin and CD44, and enhanced OSCC invasion, migration, and EMT via autocrine HSP27/TLR4 signaling. Collectively, HSP27/IL-6 axis facilitates OSCC chemoresistance, invasion, and migration by orchestrating macrophages through a positive feedback loop. We identify the regulatory mechanism underlying the interaction and crosstalk between OSCC cells and TAMs mediated by the HSP27/IL-6 axis. Targeting the HSP27/IL-6 axis could be a promising treatment strategy for OSCC patients, potentially controlling disease progression and improving prognosis and recurrence outcomes.