Focused Acoustic Vortex-Mediated Sonochemotherapy for the Amplification of Immunogenic Cell Death Combined with Checkpoint Blockade to Potentiate Cancer Immunotherapy

Sonodynamic therapy (SDT) as an auxiliary modality of cancer immunotherapy enhances systemic anti-tumor immunity. However, the efficiency of SDT-mediated immunotherapy based on conventional focused ultrasound (FUS) is restricted by the tiny focal region of FUS. Focused acoustic vortex (FAV) possessing a larger focal region, can induce stronger cavitation and thermal effects than FUS with the same parameters, having the potential to overcome this issue. This research investigated the feasibility of FAV-mediated sonochemotherapy combined with the immune checkpoint blockade (ICB) to reshape immunosuppressive tumor microenvironment (TME), inhibit tumor growth and lung metastasis. Sonosensitizer chlorin e6 (Ce6) and chemotherapeutic agent doxorubicin (Dox) were co-loaded into microbubble-liposome complex to compose Ce6/Dox@Lip@MBs (CDLM) for "all-in-one" synergistic sonochemotherapy, whose main components were clinical approved. FAV-activated CDLM significantly enriched immunogenic cell death (ICD) inducers in tumors and amplified ICD of cancer cells compared with FUS-activated CDLM. Furthermore, the amplified-ICD combined with ICB increased the infiltration of cytotoxic T lymphocytes and natural killer cells, polarized M2 macrophages to M1 macrophages, and decreased regulatory T cells. This study provides a multifunctional strategy for enriching ICD inducers in tumors and amplifying ICD to ameliorate immunosuppressive TME and potentiate systemic anti-tumor immunity.