The receptor tyrosine kinases of the tyrosine kinase receptor 3 (TYRO-3), tyrosine-protein kinase receptor UFO (AXL), and MER proto-oncogene tyrosine kinase (MerTK) (TAM) family have shown important roles in tumor progression. AXL activation promotes oncogenesis and drug resistance in cancer cells, while MerTK suppresses immune responses in macrophages (MΦ) through interactions with phosphatidylserine (PS) exposing cancer cells. Inhibition of the signaling mediated by the TAM receptors has attracted much attention in cancer immunotherapy and chemotherapy; however, few studies have investigated simultaneous inhibition of all the signaling through targeting growth arrest-specific 6 (GAS6), a common ligand of these TAM receptors. Warfarin (WA), a traditional vitamin-K antagonist, has been shown to disrupt the carboxylation of GAS6, thereby reducing the activation of TAM receptors. We hypothesized that co-delivery of WA and doxorubicin (DOX) to tumors using WA-conjugated nanoparticles (NPs) will significantly inhibit tumor growth by sensitizing cancer cells to chemotherapy and enhancing the anti-tumor immune response, while mitigating the dose-limiting toxicities associated with both drugs. In vitro , WA sensitized cancer cells to DOX treatment. In addition, WA co-treatment inhibited PS-mediated efferocytosis of DOX-treated tumor cells by MΦ and the polarization of MΦ towards the immunosuppressive M2 phenotype. Both WA and DOX were then effectively co-loaded into a laminarin-WA-conjugated polymer (LA-WA)-based nanocarrier, promoting prolonged blood retention and enhanced drug accumulation at tumor sites. Co-delivery of the two drugs via LA-WA NPs led to significantly enhanced therapeutic efficacy and improved tumor immune microenvironment as evidenced by increased numbers of natural killer cells, decreased MΦ polarization towards M2 phenotype and enhanced MΦ activation. • Warfarin sensitized cancer cells to Doxorubicin through inhibiting the GAS6/AXL/AKT pathway. • Warfarin inhibited the efferocytosis of apoptotic tumor cells by macrophages. • Warfarin reversed the efferocytosis-mediated M2 polarization of macrophages. • LA-WA/DOX+WA NPs significantly suppressed tumor growth. • LA-WA/DOX+WA NPs reversed the immunosuppressive tumor microenvironment.
Zhang et al. (Fri,) studied this question.