Co-delivery nanoparticle targeting CAF for simultaneous activating T cell plus NKT cell attack in solid tumor

INTRODUCTION: Tumor fibrosis promotes immunosuppression by creating physical barrier that limits immune cell infiltration, posing challenges for immunotherapy. Therefore, it is essential to design a reasoned therapeutic strategy to surmount the tumor immune privilege by activating antitumor immunity and simultaneously destroying the physiological barriers of tumor microenvironment. OBJECTIVES: Aim to develop a fibroblast-activated protein-α (FAP-α) responsive nanoparticle delivery system, (α-GC/NAV)-CPC, which encapsulates navitoclax (NAV) and alpha-galactosylceramide (α-GC). Upon reaching tumor site, the nanoparticles would be disassembled by FAP-α in tumor. The released α-GC activates natural killer T (NKT) and in parallel, the released NAV eliminates cancer associated fibroblasts (CAFs), ultimately breaking down physical barrier and realizing potent anti-tumor activity. METHODS: To maintain the self-assembly ability and FAP-α responsiveness, the designed amphiphilic block polymers consist of PEG chain as the hydrophilic domain, terminal cholesterol as the hydrophobic domain and FAP-α degradable amino acid residue sequence linkage (Ala-Thr-Gly-Pro-Ala). At the tissue level, the tumor specific fibrosis barrier destroying ability of (α-GC/NAV)-CPC was investigated. Subsequently, the NAV and α-GC were co-encapsulated into nanoparticles. The tumor accumulation, tumoricidal and anti-metastasis efficacy were validated in triple negative breast cancer-bearing models. RESULTS: This strategy can efficiently break down the cancer associated fibroblast based physical barrier. Encapsulated NAV can significantly decrease tumor interstitial fluid pressure (IFP), indicating as 4.9-fold lower than saline control group. Consequently, enhanced tumor infiltration and penetration of immune cells were observed. By quantitative flow-cytometry analysis, the abundances of NKT and T cells in tumors after (NAV/α-GC)-CPC treatment increased over 5 times and 4 times respectively, compared with saline treatment. Encouragingly, in in vivo models, (α-GC/NAV)-CPC treatment even led to 66.7% of mice achieving tumor eradication without recurrence. In further pulmonary metastasis challenge, mice treated with (α-GC/NAV)-CPC rarely displayed lung metastatic nodules.