Abstract
Ligands for the aryl hydrocarbon receptor (AhR), such as kynurenine derived from the tumor microenvironment, are well-known immunosuppressants. Although systemic AhR inhibition has demonstrated antitumor activity in previous studies, the specific effects of targeting AhR in dendritic cells (DCs) remain unclear. Here, we identified a CD11c-targeting peptide (SP65) with high specificity for DCs using phage display. SP65-functionalized liposomes showed enhanced drug uptake and selectivity for DCs both in vitro and in vivo. Incorporating the AhR inhibitor CH223191, we developed SP65-lipo-CH, which promoted IL-12 secretion in DCs. When co-cultured with SP65-lipo-CH–pretreated DCs, natural killer (NK) cells exhibited increased IFN-γ production and tumor-killing activity. In MC38 and metastatic LLC mouse models, SP65-lipo-CH alone suppressed tumor growth and prolonged survival. These findings suggest that SP65-lipo-CH effectively targets DCs to modulate innate immunity, representing a promising strategy for cancer immunotherapy. Through specific interaction between SP65 and CD11c, CH223191 is specifically transported to DCs. This inhibits AhR function, promoting IL-12 and IFN-γ production in DCs and NK cells, respectively.