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

Shuaiqi Feng1, Yan Chen2, Huicong Tang1

  • 1Institute of Biopharmaceutical Research, Shandong Provincial Key Laboratory of Applied Technology for Protein and Peptide Drugs, State Key Laboratory of Macromolecular Drugs and Large-Scale Preparation, Liaocheng University, Liaocheng 252000, P. R. China.

Journal of Medicinal Chemistry
|July 4, 2026
PubMed

Insights

New platinum(IV) complexes targeting epithelial-to-mesenchymal transition (EMT) and the immunosuppressive tumor microenvironment (TME) show potent anti-metastatic effects. The lead compound induces DNA damage, apoptosis, and reprograms the TME for enhanced anti-tumor immunity.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Epithelial-to-mesenchymal transition (EMT) and an immunosuppressive tumor microenvironment (TME) are critical for tumor metastasis.
  • Targeting both EMT and TME simultaneously offers a promising strategy for cancer therapy.

Purpose of the Study:

  • To develop novel Telmisartan (TELM) platinum(IV) complexes designed to simultaneously target EMT and tumor immunity.
  • To identify a lead candidate with potent anti-metastatic and anti-proliferative activities.

Main Methods:

  • Synthesis and screening of Telmisartan platinum(IV) complexes.
  • In vitro and in vivo evaluation of antiproliferative and antimetastatic activities.
  • Assessment of DNA damage, apoptosis pathways (Bcl-2/Bax/caspase-3), and signaling pathways (Ang II/AT1R, JAK2/STAT3, ERK1/2, HIF-1α/VEGFA, MMPs).
  • Analysis of EMT markers (E-cadherin, N-cadherin, Vimentin) and TME modulation (PD-L1, immunogenic cell death, T cell infiltration).

Main Results:

  • A lead Telmisartan platinum(IV) complex demonstrated significant in vitro and in vivo antiproliferative and antimetastatic efficacy.
  • The complex induced DNA damage, upregulated γ-H2AX and p53, and triggered apoptosis via the mitochondria-mediated pathway.
  • It suppressed the Ang II/AT1R axis, downregulated JAK2/STAT3 and ERK1/2, and reversed the hypoxic microenvironment by inhibiting HIF-1α/VEGFA and MMPs.
  • EMT was abrogated, evidenced by altered E-cadherin, N-cadherin, and Vimentin expression.
  • The TME was reprogrammed, characterized by PD-L1 blockade, induced immunogenic cell death, and increased CD3+/CD8+ T cell infiltration.

Conclusions:

  • The developed Telmisartan platinum(IV) complex effectively targets both EMT and the immunosuppressive TME.
  • This dual-targeting strategy holds significant potential for overcoming tumor metastasis and enhancing anti-tumor immunity.

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