In our study, we applied thermal High-Intensity Focused Ultrasound (HIFU) and mechanical HIFU for the treatment of breast cancer in murine models. This approach led to a notable increase in IL2RB expression among CD8+ T cells within the tumor microenvironment, suggesting a potential immunomodulatory effect. Further investigation revealed that this upregulation was associated with the activation of the JAK-STAT signaling pathway, a key mediator of immune responses. Building on these findings, we then explored the synergistic potential of combining IL-2 with HIFU. Our results indicated that this combined therapeutic strategy yielded significantly enhanced tumor regression in mouse models of breast cancer, outperforming the effects observed with either modality alone. This suggests that the integration of HIFU with IL-2 may offer a promising avenue for improving breast cancer treatment outcomes.