Immunomodulatory microbubbles targeting integrin αvβ3 in combination with immunotherapy for the theranostic of anaplastic thyroid cancer in mice.

Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid malignancy and currently lacks effective treatment options. While anti-PD1 therapy has shown remarkable clinical results in some cases, only a subset of ATC patients responds to it. Eganelisib (IPI549), a highly selective PI3Kγ inhibitor, can alleviate the tumor immunosuppressive state by reducing the proportion of M2-like tumor associated macrophages, partially overcoming patient resistance to anti-PD1 therapy and synergizing with its efficacy. However, the dose-dependent hepatotoxicity of IPI549 limits its utility in combination immunotherapy. To address this challenge, we developed integrin αvβ3 targeted microbubbles loaded with IPI549 and indocyanine green, abbreviated as IPI549@αIMBs. This platform enables dual modal ultrasound-fluorescence imaging for monitoring its drug release and distribution, while its combination with ultrasound targeted microbubble destruction(UTMD) technology facilitates the precise delivery and controlled release of IPI549, thereby enhancing synergy with anti-PD1 therapy and improving treatment safety. Our results demonstrate that IPI549@αIMBs effectively targeted to subcutaneous ATC tumors in mice, significantly enhancing IPI549 delivery efficiency. UTMD mediated delivery using IPI549@αIMBs combined with anti-PD1 therapy markedly inhibited subcutaneous ATC tumor growth in mice, effectively reduced the proportion of M2-like tumor associated macrophage, and increased CD8 T cell infiltration, which alleviated the tumor immunosuppressive state. In summary, this study explored a novel therapeutic strategy for ATC, demonstrating the efficacy of the IPI549@αIMB-based UTMD approach combined with anti-PD1 therapy and validating the underlying immunomodulatory mechanisms.