Fluorocarbon Modified Chitosan to Enable Transdermal Immunotherapy for Melanoma Treatment

Abstract Despite the rapid development of the immune checkpoint blockade (ICB) in melanoma treatment, the immunosuppressive tumor microenvironment (TME) still hinders the efficacy of immunotherapy. Recently, using agonists to modulate the TME have presented promising clinical responses in combination with ICB therapies. However, local intratumoral injection as the commonly used administration route for immune agonists would lead to low patient compliance. Herein, it is demonstrated that fluorocarbon modified chitosan (FCS) can self‐assemble with immune adjuvant polyriboinosinic:polyribocytidylic acid (poly(I:C)), forming nanoparticles that can penetrate through cutaneous barriers to enable transdermal delivery. FCS/poly(I:C) can efficiently activate various types of cells presented on the transdermal route (through the skin into the TME), leading to IRF3‐mediated IFN‐β induction in the activated cells for tumor repression. Furthermore, transdermal FCS/poly(I:C) treatment can significantly magnify the efficacy of the programmed cell death protein 1 (PD‐1) blockade in melanoma treatment through activating the immunosuppressive TME. This study approach offered an attractive transdermal approach in combined with ICB therapy for combined immunotherapy, particularly suitable for melanoma treatment.