Selenadiazole derivative-loaded metal azolate frameworks facilitate NK cell immunotherapy by sensitizing tumor cells and shaping immuno-suppressive microenvironments.

The low sensitivity of tumor cells and immunosuppressive microenvironments lead to unsatisfactory efficacy of natural killer (NK) cell immunotherapy. In this work, we developed a safe and effective combination treatment strategy by integrating a selenadiazole derivative (PSeD)-loaded metal azolate framework (PSeD@MAF-4(R)) with NK cells derived from cancer patients against a xenograft human breast tumor model. Intriguingly, it was found that only PSeD@MAF-4(R) pretreatment on tumor cells exhibited synergistic effects with NK cells in inhibiting tumor cell growth by up-regulating NKG2D and its ligands to maximize the interactions between NK and MCF-7 cells. Moreover, PSeD@MAF-4(R) pretreatment could significantly enhance the degranulation of NK cells and regulate their secretions of pro- or anti-inflammatory cytokines ( e.g. IL-6, IL-10, and TGF-β). Furthermore, PSeD@MAF-4(R) could significantly enhance the penetration capability of NK cells into tumor spheroids. The combination treatment mainly induced G1 phase arrest and activated multiple caspase-mediated apoptosis of tumor cells. In vivo evidence showed that PSeD@MAF-4(R) combined with NK cells could highly efficiently combat breast tumor progression via inducing and activating innate immune cell (DC and NK cell) infiltrations within tumor tissues while shaping the suppressive tumor microenvironment by down-regulating the expression of TGF-β. This developed strategy may provide important information for developing NK cell-based combination cancer immunotherapy with high efficacy and good safety profiles.