Autophagy-targeted Pt(IV) agents: a new horizon in antitumor drug development

Pt(IV) complexes as prodrugs of Pt(II) drugs exhibit numerous advantages such as enhanced stability, reduced toxicity, increased oral bioavailability, and efficacy in overcoming the drug resistance of Pt(II) compounds, which underscore their significant potential in the advancement of novel Pt anticancer agents. Furthermore, protective autophagy is pivotal in sustaining tumor cell homeostasis and modulating the tumor microenvironment (TME), thereby representing a critical target for the development of antitumor drugs. Specific inhibition or activation of autophagy during chemotherapy would break the internal homeostasis in the TME and increase antitumor activities. Consequently, developing novel Pt(IV) antitumor agents with autophagy-targeting capabilities by incorporating autophagy-regulating moieties into the Pt(IV) framework has emerged as a hot topic in the discovery of novel Pt drugs. Herein, the research progress in novel Pt(IV) antitumor drugs with autophagy-targeted properties is systematically reviewed based on the literature. The future challenges and perspectives of this fascinating class of conjugates are also discussed, aiming to provide new insights and approaches for the future design and investigation of novel Pt antitumor drugs.