Iterative Design of a Prodrug Nanocarrier for Cell Cycle Arrest, Immune Modulation, and Enhanced T Cell Infiltration for Colon Cancer Therapy

This is the authors' abstract. We don't add key points for this paper.

Recent advancements in cancer therapy have highlighted the dual role of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in both cell cycle regulation and immune activation. However, applying CDK4/6i to immunologically unfavorable tumors is challenging due to the complex tumor microenvironment (TME), characterized by inadequate T cell recruitment and exclusion mechanisms that hinder an effective antitumor immunity. In this work, we iteratively designed prodrug liposomal nanocarriers that integrate multiple functions: cell cycle inhibition through encapsulation of CDK4/6i, immune activation via concurrent delivery of an oral gavage-inducing chemotherapy agent, and overcoming T cell exclusion through the incorporation of a cholesterol prodrug. This iterative nanocarrier design effectively improves the pharmacokinetic profile of CDK4/6i, overcomes the immunosuppressive TME, achieves superior antitumor efficacy, and synergizes with immune checkpoint inhibitors to provide lasting effects in various colon cancer animal models.