Self-assembled natural triterpenoids for the delivery of cyclin-dependent kinase 4/6 inhibitors to enhance cancer chemoimmunotherapy.

Immunogenic cell death (ICD) has recently emerged as a promising strategy in reinforcing anti-PD-L1 blockade immunotherapy of triple-negative breast cancer (TNBC). The CDK4/6 inhibitor palbociclib (PAL), as a clinical star medicine targeting the cell cycle machinery, is an ideal candidate for fabricating a highly efficient ICD inducer for TNBC chemoimmunotherapy. However, the frequently observed chemoresistance and clinical adverse effects, as well as significant antagonistic effects when co-administered with certain chemotherapeutics, have seriously restricted the efficiency of PAL and the feasibility of combination strategies. Herein, we screened and identified six self-assembled natural pentacyclic triterpenoid (PT) molecules that can serve as competent co-administration nanoplatforms for the synergistic or combined delivery of PAL. Analysis of two representative PT-PAL nano-assemblies validated that PT-mediated co-assembly enhances the cytotoxicity and synergy of PAL by inhibiting the PI3K/AKT/mTOR signaling pathway, rather than directly targeting CDK4/6 proteins. Importantly, the PAL nanoassemblies exhibited multiple favorable therapeutic features and stronger accumulative ICD induction, ensuring highly efficient synergistic anti-PD-L1 chemoimmunotherapy by simultaneously facilitating T-cell immune response and reversing the immunosuppressive tumor microenvironment. This study offers possibilities for improving the anticancer efficacy of CDK4/6 inhibitors and potential avenues for clinical applications of chemoimmunotherapy in treating TNBC.