Synergistic anticancer immunity in metastatic triple-negative breast cancer through an in situ amplifying Peptide-Drug Conjugate.

Despite significant progress in combining cancer immunotherapy with chemotherapy to treat triple negative breast cancer (TNBC), challenges persist due to target depletion and tumor heterogeneity, especially in metastasis. Chemotherapy lacks precise targeting abilities, and targeted therapy is inadequate in addressing the diverse heterogeneity of tumors. To address these challenges, we introduce RGDEVD-DOX as a tumor-specific immunogenic agent, namely TPD1, which targets integrin αvβ3 and gets continuously activated by apoptosis. TPD1 facilitates the caspase-3-mediated in situ amplification that results in tumor-specific accumulation of doxorubicin. This local concentration of doxorubicin induces immunogenic cell death and promotes the recruitment of immune cells to the tumor site. Notably, the tumor-targeting capabilities of TPD1 help bypass the systemic immunotoxicity of doxorubicin. Consequently, this alters the tumor microenvironment, converting it into a 'hot' tumor that is more susceptible to immune checkpoint inhibition. We demonstrated the anti-metastatic and anti-cancer efficacy of this treatment using various xenograft and metastatic models. This study underscores the high potential of caspase-3 cleavable peptide-drug conjugates to be used in conjunction with anti-cancer immunotherapies. Metastatic TNBC targeting strategy of TPD1 utilizing focused immune stimulation and caspase-3 mediated amplification cycle. [Display omitted] • Demonstrated effective induction of immunogenic cell death and enhanced immunogenicity in tumors. • Achieved effective targeted drug delivery utilizing the caspase-3 mediated activating cycle. • Successfully targets both primary tumors and metastasis in diverse mice TNBC models. • Shows synergistic anticancer efficacy when combined with anti-PD1 treatments. • Exhibits minimal immunotoxic effects compared to doxorubicin, ensuring safer combination therapies. [ABSTRACT FROM AUTHOR]