Engineered antler stem cells derived exosomes potentiate anti-tumor efficacy of immune checkpoint inhibitor by reprogramming immunosuppressive tumor microenvironment

Immunotherapy has received extensive attention in the field of tumor treatment, but the existence of immunosuppressive tumor microenvironment (TME) leads to the suboptimal therapeutic effect, which is the main obstacle that restricts the clinical application of immunotherapy. Therefore, there is an urgent demand to reverse the immunosuppressive TME to improve the anti-tumor efficacy. In this work, engineered antler stem cells (ASCs)-derived exosomes were developed by modified with M2 macrophage targeting peptide (M2Pep) on their surface and encapsulated with toll-like receptor 3 (TLR3) agonist poly(I:C) termed as M2Pep-Exo(pIC) for enhanced tumor immunotherapy. The natural nanocarrier exosomes derived from ASCs hold great potential to suppress tumor growth and are easily to be obtained because of the tumor resistance and annual regeneration characteristics of the antler. Due to the engineering of M2Pep, the M2Pep-Exo(pIC) achieved improved enrichment in tumor tissue. The M2Pep-Exo(pIC) could boost systemic anti-tumor immune responses through repolarizing tumor associated macrophages (TAMs) and promoting dendritic cells maturation, leading to an increased cytotoxic CD8(+) T cells infiltration in tumor site for effective anti-tumor therapy. Moreover, the combination of M2Pep-Exo(pIC) with the PD-L1 antibody not only arrested the progression of primary tumor, but also inhibited tumor metastasis. These findings highlight a promising approach to enhance PD-L1 checkpoint blockade activity through remodeling immunosuppressive TME, thus achieving a robust immunotherapy effect for solid tumors.