Reactive oxygen species-responsive dual-targeted nanosystem promoted immunogenic cell death against breast cancer

The development of an optimal treatment modality to improve the therapeutic outcome of breast cancer patients is still difficult. Poor antigen presentation to T cells is a major challenge in cancer immunotherapy. In this study, a synergistic immunotherapy strategy for breast cancer incorporating immune cell infiltration, immunogenic cell death (ICD), and dendritic cell (DC) maturation through a reactive oxygen species (ROS)-responsive dual-targeted smart nanosystem (anti-PD-L1-TKNP) for the simultaneous release of DOX, R848, and MIP-3 alpha in the tumor microenvironment is reported. Following local injection, anti-PD-L1-DOX-R848-MIP-3 alpha/thioketal nanoparticle (TKNP) converts tumor cells to a vaccine owing to the combinatorial effect of DOX-induced ICD, R848-mediated immunostimulatory properties, and MIP-3 alpha-induced immune cell recruitment in the tumor microenvironment. Intratumoral injection of anti-PD-L1-DOX-R848-MIP-3 alpha/TKNP caused significant regression of breast cancer. Mechanistic studies reveal that anti-PD-L1-DOX-R848-MIP-3 alpha/TKNP specifically targets tumor tissue, resulting in maximum exposure of calreticulin (CRT) and HMGB1 in tumors, and significantly enhances intratumoral infiltration of CD4(+) and CD8(+) T cells in tumors. Therefore, a combined strategy using dual-targeted ROS-responsive TKNP highlights the significant application of nanoparticles in modulating the tumor microenvironment and could be a clinical treatment strategy for effective breast cancer management.

Automated summary

This study reports a synergistic immunotherapy strategy for breast cancer using a reactive oxygen species-responsive dual-targeted smart nanosystem that releases multiple substances in the tumor microenvironment to enhance immune cell infiltration and convert tumor cells into a vaccine. The strategy significantly regressed breast cancer and improved therapeutic outcome by enhancing immune cell infiltration.