HMGB1-Induced Metabolic Rewiring of Macrophages via RAGE/MAPK Fosters Endocrine Resistance in Breast Cancer

Endocrine resistance remains a critical challenge in hormone receptor-positive (HR+) breast cancer. The impact of the immune microenvironment on endocrine therapy efficacy is increasingly recognised, but its mechanisms are not fully understood. Here, we investigated that nuclear HMGB1 expression in tumour cells was closely associated with endocrine therapy resistance in HR+ breast cancer using tumour genomic databases. Specially, tumours with high HMGB1 expression induced M2-like macrophage polarisation, which was related to HMGB1 paracrine signalling. Mechanistically, HMGB1 bound to the RAGE receptor on macrophages, activating the downstream MAPK signalling pathway and was closely linked to the activation of fatty acid metabolism pathways. Macrophages co-cultured with high-HMGB1 tumour cells exhibited metabolic characteristics associated with carcinogenesis, a loss of glycolytic intermediates and a shift toward a pro-tumourigenic metabolic state compared to those co-cultured with low-HMGB1 cells. Co-culture with M2-like macrophages significantly activated growth signalling pathways like NF-κB in the high-HMGB1 tumour cells. Taken together, high expression of HMGB1 in tumour cells promotes fatty acid metabolic remodelling and functional polarisation in macrophages, contributing to endocrine therapy resistance in HR+ breast cancer. HMGB1 acts as a candidate for immune mediator and paved a way to develop potential target drug.