Resolve and regulate: Alum nanoplatform coordinating STING availability and agonist delivery for enhanced anti-tumor immunotherapy

Abstract

The stimulator of interferon genes (STING) pathway represents a promising target in cancer immunotherapy. However, the clinical translation of cyclic dinucleotide (CDN)-based STING agonists remains hindered by insufficient formation of functional CDN-STING complexes. This critical bottleneck arises from two interdependent barriers: inefficient cytosolic CDN delivery and tumor-specific STING silencing via DNA methyltransferase-mediated promoter hypermethylation. To overcome this, we engineered DecG@Al, a dual-action platform combining clinically approved aluminum hydroxide (Alum), the CDN agonist 2'3'-cGAMP, and the DNA demethylating agent decitabine. Alum enhances 2'3'-cGAMP transmembrane delivery while improving decitabine bioavailability for epigenetic STING restoration, synergistically amplifying intracellular CDN-STING complexes and STING pathway activation. In B16F10 melanoma models, DecG@Al reprogrammed the immunosuppressive microenvironment by skewing macrophages toward a pro-inflammatory M1 phenotype, activating dendritic cells, and reducing CD8⁺ T cell exhaustion. Transcriptomic analysis revealed broad immune activation, including upregulated pro-inflammatory chemokines in tumor-associated macrophages. This immunomodulation translated to potent tumor suppression, prolonged survival, and minimal systemic toxicity. By coupling STING agonist delivery and receptor restoration, DecG@Al addresses the root cause of CDN-STING complex insufficiency, offering a clinically translatable strategy to reignite antitumor immunity.

Keywords: 2′3′-cGAMP; Alum; Anti-tumor immunotherapy; Decitabine; STING.