VEGFB₁₆₇ drives tumor progression by modulating the immune microenvironment

Vascular endothelial growth factor B (VEGFB), a member of VEGF family, shares the VEGFR1 receptor with VEGFA. VEGFB has two isoforms, VEGFB₁₆₇ and VEGFB₁₈₆, whose distinct biological roles remain poorly characterized. To elucidate the isoform-specific functions of VEGFB in tumorigenesis, we utilized transgenic mouse models, including VEGFB overexpression (aP2-Vegfb₁₆₇, aP2-Vegfb₁₈₆) and VEGFB knockout (Vegfb^-/-), along with tumor cell lines (B16-F10, U14 and LLC). Our findings revealed that VEGFB₁₆₇ acts as a potent promoter of tumor growth. VEGFB inactivation significantly retards tumor growth and tumor cell metastasis. Mechanistically, VEGFB deficiency alters the tumor microenvironment by shifting tumor-associated macrophages (TAMs) from a pro-tumor M2 phenotype to an anti-tumor M1 phenotype, thereby enhancing anti-tumor immunity. Notably, the impact of VEGFB on tumor growth and metastasis surpasses that of VEGFA, highlighting its potential as a promising therapeutic target. These findings establish VEGFB₁₆₇ as a key regulator of tumor progression and suggest that targeting VEGFB signaling could provide novel strategies for VEGFB-sensitive cancers.