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.