"Closed-Loop" O₂-Economizer Induced <i>In Situ</i> Therapeutic Vaccine against Hypoxic Tumors.

Abstract

Therapeutic tumor vaccines, which use tumor antigens to stimulate a cancer patient's immune system to eventually kill the tumor tissues, have emerged as one of the most attractive strategies in anticancer research. Especially, exploring <i>in situ</i> vaccines has become a potential field in cancer immunotherapy. However, due to the hypoxic tumor microenvironment, the generation of tumor antigens is always mild and not sufficient. Hence, in this study, we designed a closed-loop mitochondrial oxygen-economizer (TPCA) to induce enhanced phototherapy-driven <i>in situ</i> vaccines. The O₂-economizer was developed by the integration of the photosensitizer CyI and the mitochondrial inhibitor atovaquone into the PAMAM dendrimer. <i>In vitro</i> and <i>in vivo</i> studies showed that TPCA could enter the mitochondria through (3-propylcarboxyl) triphenylphosphine bromide (TPP) and effectively restrict the respiration of tumor cells to reduce tumor hypoxia, thus providing continuous oxygen for enhanced iodinated cyanine dye mediated photodynamic therapy, which could further induce <i>in situ</i> vaccines for ablating the primary tumor directly and inhibiting the tumor metastasis and recurrence. Furthermore, the antitumor mechanism revealed that O₂-economizer-based oxygen-boosted PDT elicited immunogenic cancer cell death with enhanced exposure and release of DAMPs and altered the immunosuppressive tumor microenvironment with increased recruitment of T cells in tumors, thereby inducing <i>in situ</i> vaccines and provoking the systematic antitumor responses against CT26 tumors. This study will provide innovative approaches for local, abscopal, and metastatic tumor treatment.