Galangin-loaded biomimetic dendritic cells membrane nanovaccine reprograms the ovarian cancer microenvironment <i>via</i> Stat3/IDO1/AhR axis to boost immunotherapy.

Abstract

Ovarian cancer, a highly lethal gynecological malignancy with high recurrence rates and low survival, poses significant treatment challenges. While immunotherapy, particularly dendritic cell (DC) vaccines, boosts immune responses, its clinical efficacy is limited by poor antigen presentation and weak lymph node targeting. To address this, we develop a novel biomimetic nanovaccine (GA-NPs@DCV) using cell membrane-coated nanoparticles that incorporate the natural anti-tumor agent galangin (GA) and ovarian tumor-associated antigens (TAAs). GA-NPs@DCV features the antigen-presenting functions of DCs and utilizes GA to induce tumor immunogenic cell death (ICD), which not only endows the vaccine with abundantly processed specific TAAs, but also ensures robust homing capability to lymph nodes and the tumor microenvironment. Interestingly, in OT-I/OT-II transgenic mice, GA-NPs@DCV enhances the proliferation of CD8⁺ and CD8⁺ IFN-γ⁺ cells to activate potent immune responses. Furthermore, a nano-DC vaccine carrying distinct antigens (NPs@DCV) not only inhibits tumor growth and activates systemic immune responses, but also effectively prevents tumor recurrence. Importantly, GA-NPs@DCV exerts potent anti-ovarian cancer effects by promoting immune activation, inhibiting immune evasion through the Stat3/IDO1/AhR signaling axis, and remodeling tumor immune microenvironment <i>via</i> regulation of the tryptophan metabolic pathway. Notably, GA-NPs@DCV also promotes the generation of tissue-resident memory T cells (T_RM, CD8⁺CD103⁺ cells) within tumor tissue, effectively inducing long-term protective immunity. Overall, these findings identify GA-NPs@DCV as an effective personalized nanovaccine that can simultaneously deliver tumor antigens and the Stat3 inhibitor GA to the tumor microenvironment to exert potent antitumor effects, providing a promising immunotherapeutic strategy for ovarian cancer.