Targeting the hypoxia‐inducible factor‐1 alpha‐exoVEGF axis in tumor‐associated macrophages overcomes Bacillus Calmette‐Guérin immunotherapy resistance

Abstract Bacillus Calmette‐Guérin (BCG) immunotherapy is limited by resistance in ∼50% of patients, linked to tumor microenvironment (TME) angiogenesis. The work explored if BCG‐activated tumor‐associated macrophages (TAMs) drive angiogenesis via hypoxia‐inducible factor‐1α (HIF‐1α) to impair BCG efficacy. Results demonstrated that macrophages stimulated with BCG significantly enhanced the proliferation, migration, and tube formation of endothelial cells. Further mechanistic studies revealed that this pro‐angiogenic effect was mediated through the activation of the NF‐ κ B, PI3K/AKT and p38/MAPK signaling pathways. Activation of these pathways subsequently led to the upregulated expression of HIF‐1α and vascular endothelial growth factor A (VEGFA). Critically, HIF‐1α deficiency in macrophages effectively inhibited BCG‐induced angiogenesis without exerting a significant impact on the infiltration of CD8 + T cells or B cells. Additionally, BCG stimulation enhanced the secretion of VEGF encapsulated in exosomes in an HIF‐1α‐dependent manner, and these VEGF‐enriched exosomes further facilitated the activation of endothelial cell functions. In conclusion, the present study confirms that BCG can promote tumor angiogenesis by activating macrophages to induce the release of exosome‐derived VEGF through an HIF‐1α‐dependent pathway. Targeting the HIF–1α‐exosome‐derived VEGF (HIF‐1α–exoVEGF) axis holds promise as a potential strategy to overcome BCG resistance and improve its therapeutic efficacy.