Engineered cell nanovesicle antagonists for androgen deprivation therapy of melanoma

Abstract

Epidemiological studies on melanoma have revealed significant gender disparities, with the incidence and mortality rates being higher in males than in females. Recent studies indicate that androgen contributing to T cell exhaustion and promoting cancer cell proliferation. While clinical androgen deprivation therapies (ADT),particularly the use of androgen receptor (AR) antagonists to block AR signaling, has been employed in clinical settings to reduce androgen levels, antiandrogen drugs often encounter challenges such as poor targeting and selectivity, increased toxicity, low stability, short half-life and the emergence of drug resistance. Here, we establish a nanoantagonists for efficient AR signaling blockade by arming antigen-activated dendritic cells (DCs) nanovesicles with AR antibodies (aAR-NV_OVA). This innovative approach demonstrates dual therapeutic efficacy: aAR-NV_OVA effectively disrupts androgen-AR interactions in both melanoma cells and T cells, simultaneously inhibiting tumor proliferation and reversing T cell exhaustion. Furthermore, aAR-NV_OVA retains the inherent immunostimulatory properties of DCs, facilitating T cell activation and enhancing cytotoxic T lymphocyte infiltration within tumor tissues. As a result, a synergistic effect has been observed in boosting T cell-based immunotherapy by simultaneously enhancing T cell activity and reducing its exhaustion. Our study using aAR-NV_OVA to antagonize androgen effects offers a promising new strategy for enhancing melanoma immunotherapy.