Blockade of neutrophil recruitment to tumor sites based on sialic acid-modified nanoplatforms enhances the efficacy of checkpoint blockade immunotherapy

Abstract

Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment, relying on the immune system to control and kill tumors. However, accumulating evidence indicates that tumor-infiltrating neutrophils impede the proliferation and activation of T cells and determine the resistance to checkpoint blockade and chemotherapy. In this study, sialic acid ligand-modified colchicine derivative phospholipid complexes specifically targeted tumor-associated neutrophils in the peripheral blood, blocked neutrophil accumulation in tumors, and attenuated the inhibitory effect of infiltrating neutrophils on T cells. Neutrophil blocking therapy enhanced the immunotherapy effect of the PD-L1 antibody in S180 advanced tumors and 4T1 breast cancer. Our study found that PD-L1 antibody monotherapy increased the tumor infiltration of immunosuppressive neutrophils. Combination therapy with neutrophil blocking can greatly reduce tumor-infiltrating neutrophils and increase the proliferation of cytotoxic CD8⁺ T lymphocytes in the tumor. The combination therapy significantly improved the survival rate of mice with advanced S180 tumors and increased the sensitivity of immune checkpoint inhibitors to 4T1 cold tumors.