Tumor cell membrane‑coated MOF‑199 nanoparticles co‑loaded with auranofin and celecoxib enhance single‑dose radiotherapy and anti‑PD‑L1 therapy in cervical cancer

Cervical cancer (CC) remains one of the leading causes of cancer-related death among women worldwide. Radiotherapy (RT) is an integral component of multimodal treatment for CC. Beyond its direct cytotoxic effects mediated by radiation-induced DNA damage, RT can also elicit antitumor immunity by promoting the generation of reactive oxygen species (ROS) and inducing immunogenic cell death (ICD). This immunomodulatory property provides a strong rationale for combining RT with immune checkpoint inhibitors (ICIs), a combination strategy that holds promise for enhancing therapeutic efficacy in CC. However, CC cells can exploit their antioxidant defense systems to counteract the oxidative stress induced by RT. The glutathione (GSH) and thioredoxin 1 (Trx1) antioxidant systems constitute the major intracellular antioxidant barriers of CC. They can attenuate ICD by scavenging ROS to limit RT-induced antitumor immune activation, thereby diminishing the efficacy of RT and ICIs combination treatment. Additionally, RT can also activate cyclooxygenase-2 (COX-2) to promote the production and release of prostaglandin E2 (PGE2), in turn suppressing DC maturation, consequently weakening ICD-mediated activation of anti-tumor immunity. Hence, we herein designed a tumor cell membrane-coated copper-based metal-organic framework nanomaterial (MOF-199) co-delivering auranofin and celecoxib (MAC@M) for co-targeting the antioxidant system and COX-2/PGE2 pathway to augment radioimmunotherapy efficacy in CC. In vitro experiments demonstrated that MAC@M could significantly enhance RT to increase CRT exposure, HMGB1 release, and ATP secretion, as well as promote DC activation. In animal models, MAC@M combined with RT elicited robust CD8⁺ T cell and NK cell-mediated antitumor immune responses, which largely contributed to local tumor control and a pronounced systemic antitumor effect, ultimately improving ICI efficacy in CC. Collectively, our study may provide a new combinatorial treatment strategy against CC.