Adoptive natural killer (NK) cell therapy (ANKCT) is a promising strategy for hepatocellular carcinoma (HCC); however, its efficacy is hampered by insufficient NK cell homing and the immunosuppressive activity of M2-polarized tumor-associated macrophages (TAMs). Activation of the cyclic guanosine monophosphate (GMP)–adenosine monophosphate synthase (AMP) synthase–stimulator of interferon genes (cGAS–STING) pathway enhances NK-cell recruitment and reprograms TAMs toward a proinflammatory M1 phenotype. Radiation therapy (RT) activates the cGAS–STING pathway by inducing reactive oxygen species (ROS)-mediated DNA damage. Compared with high-dose irradiation, low-dose radiotherapy (LDRT) offers advantages, including reduced toxicity and enhanced antitumor immunity. However, the robust thioredoxin (Trx) and glutathione (GSH) antioxidant systems in HCC inhibit LDRT-induced ROS accumulation, thereby limiting immune activation. These limitations highlight the need for auxiliary strategies to complement LDRT-induced immunogenicity. Here, we developed a biomimetic nanoparticle in which auranofin-loaded MOF-199 is cloaked with tumor cell membranes (A@MMOF). A@MMOF disrupts tumor redox homeostasis by irreversibly inhibiting the GSH and Trx antioxidant systems while inducing GSH-dependent Cu²⁺ release from the MOF framework. The subsequent reduction of Cu²⁺ to Cu⁺ catalyzes Fenton-like reactions, markedly amplifying the intracellular ROS levels. By providing a sustained redox-driven stimulus, A@MMOF compensates for the insufficient oxidative stress induced by LDRT, leading to robust activation of the cGAS–STING pathway. Thus, A@MMOF synergizes with LDRT to remodel the tumor microenvironment, enhance NK cell infiltration and activation, and ultimately improve the efficacy of ANKCT in HCC.
Liu et al. (Mon,) studied this question.
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