Platinum^IV Complex Enabling Multiple and Potent Tumor Microenvironment Remodeling for Cancer Chemo-Immunotherapy

Area of Science:

• Oncology
• Drug Development
• Immunotherapy

Background:

• The tumor microenvironment (TME) hinders chemotherapy effectiveness and reduces immunogenic cell death.
• Cisplatin, a chemotherapy drug, has limitations in overcoming TME-mediated resistance.
• Pirfenidone analogues show potential in modulating the TME.

Purpose of the Study:

• To develop novel platinum(IV) prodrugs integrating cisplatin and a pirfenidone analogue.
• To evaluate the efficacy of these prodrugs in overcoming TME-induced chemoresistance and enhancing immunogenic cell death.
• To assess the in vitro and in vivo antitumor activity and safety profiles.

Main Methods:

• Synthesis and in vitro evaluation of novel platinum(IV) prodrugs across multiple cancer cell lines.
• Mechanistic studies to investigate intracellular effects (glutathione depletion, P-gp suppression) and TME modulation.
• Assessment of immunogenic cell death induction, dendritic cell maturation, and in vivo antitumor efficacy and safety.

Main Results:

• Platinum(IV) prodrugs demonstrated superior anticancer activity, improved resistance profiles, and selectivity in vitro.
• Mechanistic studies confirmed TME remodeling, glutathione depletion, P-gp suppression, and induction of damage-associated molecular patterns (DAMPs).
• Prodrugs triggered immunogenic cell death and showed significantly enhanced in vivo antitumor activity (3.3-fold inhibition) with improved safety compared to cisplatin.

Conclusions:

• Novel platinum(IV) prodrugs effectively combine cytotoxic and TME-modulating functions.
• These agents overcome chemoresistance by remodeling the TME and inducing immunogenic cell death.
• The developed platinum(IV) complexes represent a promising strategy for enhanced cancer therapy with improved safety.