Development of Telmisartan Platinum(IV) Complexes for Antimetastatic Therapy: Targeting EMT and Tumor Immunity through Suppressing AT1R

The epithelial-to-mesenchymal transition (EMT) and immunosuppressive tumor microenvironment (TME) are key drivers of tumor metastasis. Here, a series of Telmisartan (TELM) platinum(IV) complexes targeting EMT and tumor immunity were developed. A lead candidate was screened out that exhibited potent antiproliferative and antimetastatic activities both in vitro and in vivo. It effectively induced DNA damage and upregulated the expression of γ-H2AX and p53, further triggering significant apoptosis via the mitochondria-mediated Bcl-2/Bax/caspase-3 pathway. Then, the Ang II/AT1R axis was suppressed by the TELM ligand. Subsequently, the JAK2/STAT3 and ERK1/2 pathways were downregulated, while the hypoxic microenvironment was also reversed by inhibiting HIF-1α/VEGFA and MMPs signaling. As a result, the EMT process was abrogated by modulating E-cadherin, N-cadherin, and Vimentin. Additionally, the immunosuppressive TME was reprogrammed by blocking the immune checkpoint PD-L1 and inducing immunogenic cell death, and the infiltration density of CD3+ and CD8+ T cells was increased in tumor tissues.