ASFV activates STAT3 to induce proviral M2 macrophage polarization

African swine fever (ASF) is an acute and highly infectious disease caused by African swine fever virus (ASFV) that has dealt a massive blow to the development of the pig industry in China. Macrophages, the primary target cells of ASFV, exhibit high plasticity. However, their phenotypic changes during infection remain poorly understood. In this study, we observed a significant increase in M2 monocytes within the peripheral blood of ASFV-infected pigs. In vitro experiments demonstrated that ASFV drives macrophage polarization toward the M2 phenotype through early phosphorylation of STAT3. STAT3 inhibition with STATTIC not only blocked M2 polarization but also suppressed ASFV replication. While M2 macrophages do not impede viral attachment or internalization, they display reduced killing capacity compared to M1 macrophages. Furthermore, in a mixed lymphocyte reaction (MLR) system, CD4⁺ T cells cocultured with ASFV-infected M2-polarized macrophages presented suppressed early activation, marked by downregulated CD25 expression, ultimately impairing adaptive immunity. These findings reveal a critical immune evasion strategy employed by ASFV and provide key insights into ASF pathogenesis and viral persistence.