Small-Molecule\nTherapeutics Achieve Multiple Mechanism-Mediated\nSensitizations of Colorectal Cancer to Immune Checkpoint Blockade\nvia Neutrophil Micropharmacies

Immune checkpoint blockade (ICB)\ntherapy has been approved\nfor\ncolorectal cancer (CRC). However, response rates are variable and\noften <50%. The low tumor immunogenicity and immunosuppressive\ntumor microenvironment (TME) jointly contribute to this suboptimal\nresponse rate. This study confirmed the potential of combining immunogenic\ncell death (ICD) inducer irinotecan (IRI) and transforming growth\nfactor-β (TGF-β) inhibitor galunisertib (GAL) to improve\ntumor immunogenicity and remodel the immunosuppressive TME. Moreover,\nto ameliorate the <i>in vivo</i> delivery barriers associated\nwith small molecules, neutrophil micropharmacies (NOG) were developed\nfor the codelivery of IRI and GAL, which loaded the commercial liposome\nformulation of IRI (ONIVYDE, ONI) intracellularly and conjugated the\npH-responsive GAL liposome (GLP) on the cell surface. This neutrophil-based\nformulation resulted in a >4-fold increase in the ratios of the\namount\nof both IRI and GAL accumulated in tumors to the dosage administration,\neffectively achieving multiple mechanism-mediated sensitization of\nCRC to ICB therapy.