Ultrasound-triggered Drug-Loaded Nanobubbles for Enhanced T Cell Recruitment in Cancer Chemoimmunotherapy

Chemotherapy combined with immunotherapy is a highly promising approach for treating tumors. However, systemic administration of chemotherapeutic drugs often fails to accumulate effectively at the tumor site and lacks sufficient immunogenicity to activate adaptive immunity, making it difficult to achieve an effective T-cell immune response within tumor microenvironment. Herein, this work develops drug-loaded nanobubbles (DTX-R837@NBs) that encapsulate the chemotherapy drug docetaxel and the immune adjuvant R837 via a thin-film hydration method. Ultrasound-targeted nanobubble destruction promoted drug accumulation within tumor tissues and damaged tumor cells through the cavitation effect, inducing immunogenic cell death and releasing damage-associated molecular patterns to augment dendritic cell maturation. Notably, DTX-R837@NBs exhibited excellent contrast-enhanced ultrasound imaging capabilities, enabling seamless integration of diagnosis and treatment. In combination with immune checkpoint blockade using programmed cell death protein 1 (PD-1), the generated immunological responses attacked residual tumor cells and ameliorated the immunosuppressive tumor microenvironment, inhibiting distant tumor growth and metastasis. Moreover, this strategy exhibited robust immune memory effects, effectively protecting the host and preventing tumor recurrence upon rechallenge. Overall, ultrasound-mediated DTX-R837@NBs combined with anti-PD-1 immune checkpoint blockade therapy exhibits robust antitumor efficiency, represents a promising strategy for overcoming immunotherapy resistance in cold tumors and warrants further investigation for clinical translation.