Multistimuli-responsive degradable metal-organic framework nanoplatform potentiates photoimmunotherapy for hepatocellular carcinoma via cGAS-STING pathway activation

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Photoimmunotherapy, which integrates photodynamic/photothermal therapy with immunomodulation, has emerged as a promising therapeutic strategy. However, its efficacy is often constrained by the immunosuppressive tumor microenvironment (TME) characteristic. Activation of the cGAS/STING signaling pathway represents a key mechanism for initiating innate immunity, thereby providing an attractive target for enhancing immunotherapy. In this study, we identified acetaminophen (APAP) as a potent in situ STING pathway activator capable of activating the cGAS/STING pathway and inducing apoptosis in HCC cells. To enable tumor-targeted delivery of APAP, we constructed a degradable nanoplatform termed GSST/APAP@HA. This system was fabricated by incorporating disulfide bonds into a Gd-TCPP-based amorphous metal-organic framework (MOF)-like networks (Gd-aMOF), loading it with APAP, and modifying the surface with hyaluronic acid (HA) for active targeting. Both in vitro and in vivo evaluations demonstrated efficient tumor accumulation of the nanoplatform and photodynamic-triggered immunogenic cell death (ICD), which provoked a robust antitumor immune response. Simultaneously, laser-induced reactive oxygen species (ROS) within the acidic TME promoted Gd-aMOF degradation and APAP release, leading to cGAS/STING pathway activation and remodeling of the immunosuppressive microenvironment. This combinatory approach resulted in significant tumor suppression in mouse HCC models. Coupled with its low cytotoxicity, excellent biocompatibility and superior magnetic resonance imaging (MRI) capability, the GSST/APAP@HA nanoplatform represents a promising theranostic strategy for cancer photoimmunotherapy.