Targeting CXCL12-CXCR4 Signaling Enhances Immune Checkpoint Blockade Therapy Against Triple Negative Breast Cancer

Insufficient T cell infiltration in triple-negative breast cancer (TNBC) has limited its response rate to immune checkpoint blockade (ICB) therapies and motivated the development of immunostimulatory approaches to enhance the ICB therapy. CXCR4 is a chemokine receptor highly upregulated both on cell surface and cytoplasm in tumor tissues. Activating CXCR4 has been associated with increased immunosuppression in the tumor microenvironment. Here, we developed a CXCR4-targeted liposomal formulation (Liposomal-AMD3100) to enhance therapeutic efficacy of AMD3100, a CXCR4 antagonist. Particularly, AMD3100 is not only encapsulated into the liposome but coated on the surface of the formulation to serve as a targeting moiety and a dual blocker capable of inhibiting CXCR4 activation extracellularly and intracellularly. The Liposomal-AMD3100 remodeled both immune and stromal microenvironment more efficiently compared with free AMD3100, indicating better pharmacodynamic profile of AMD3100 achieved by liposomal formulation. The combination of anti-PD-L1 with Liposomal-AMD3100 formulation exhibited an increased antitumor effect and prolonged survival time compared with monotherapies in a murine TNBC model (4T1). This work proves that immune activation via liposomal delivery of CXCR4 inhibitors has a great potential to expand ICB therapies to originally ICB-insensitive cancer types.

Automated summary

Insufficient T cell infiltration in triple-negative breast cancer (TNBC) has led to limited responses to immune checkpoint blockade (ICB) therapies, prompting the development of immunostimulatory approaches. A novel CXCR4-targeted liposomal formulation was developed to enhance the therapeutic efficacy of AMD3100, a CXCR4 antagonist, leading to improved immune activation and antitumor effects in a murine TNBC model when combined with anti-PD-L1 therapy.