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<p>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.</p> Graphical abstract <p></p>

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Dendritic cell-targeted liposomes for cancer immunotherapy via inhibition of aryl hydrocarbon receptor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月15日

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  • Chen-Guang Zhang,
  • Chen-Yun Yeh,
  • Sheng-Yun Hsu,
  • Mridula Prakash,
  • Adrian B. Abarientos,
  • Hsi-Ming Chiang-Hsieh,
  • You-Yu Lin,
  • Christopher Llynard D. Ortiz,
  • Lee-Wei Yang,
  • Pi-Hui Liang,
  • Han-Chung Wu,
  • Yungling Leo Lee

摘要

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.

Graphical abstract