Targeting OAS3 for reversing M2d infiltration and restoring anti-tumor immunity in pancreatic cancer

Abundant infiltration of tumor-associated macrophages (TAMs) within the tumor stroma plays a pivotal role in inducing immune escape in pancreatic cancer (PC). Lactate serves as a direct regulator of macrophage polarization and functions, although the precise regulation mechanism remain inadequately understood. Our study revealed that PC cells promote macrophage polarization towards the M2d phenotype through high lactate secretion. M2d is characterized by elevated secretion of IL-10 and VEGF-A, which diminish CD8 ⁺ T cells cytotoxicity and promote tumor neoangiogenesis simultaneously. Additionally, we identify 2,5’-oligoadenylate synthase 3 (OAS3) as an essential regulator of M2d polarization, upregulated by PC cells via lactate/METTL3/OAS3 axis. METTL3 mediated m ⁶ A modification on OAS3 mRNA correlates with increased OAS3 expression in TAMs, which is associated with poorer prognosis in PC patients. OAS3 deficiency in macrophages substantially impairs IL-10 ^high VEGF-A ^high M2d polarization and their pro-tumor functions while enhancing the therapeutic efficacy of gemcitabine (Gem) and anti-PD-L1 mAb in humanized mouse models. In conclusion, OAS3 presents as a promising immune therapeutic target for reversing IL-10 ^high VEGF-A ^high M2d infiltration and restoring CD8 ⁺ T cell mediated anti-tumor immunity in pancreatic cancer.