KAT6A inhibitor-loaded and anti-PD-L1-coated manganese metal–organic framework nanoplatform for enhanced colorectal cancer immunotherapy via cGAS-STING activation

Abstract

Colorectal cancer immunotherapy remains limited by insufficient innate immune activation, poor tumor immune infiltration, and resistance to immune checkpoint blockade. Herein, we developed a KAT6A inhibitor-loaded and anti-PD-L1-coated manganese metal-organic framework (MnMOF) nanoplatform for enhanced colorectal cancer immunotherapy through coordinated cGAS-STING activation and PD-L1 blockade. The KAT6A inhibitor (Ki) PF-9363 was loaded into MnMOF, followed by surface modification with anti-PD-L1 antibody to obtain Ki@MnMOF@P. The nanoplatform exhibited efficient Ki loading, pH-responsive drug release, and retained PD-L1 blocking activity. In vitro, Ki@MnMOF@P showed enhanced cellular uptake and selective cytotoxicity against HCT116 cells while maintaining low toxicity toward normal colonic epithelial NCM460 cells. In a CT26 colorectal tumor-bearing mouse model, systemic administration of Ki@MnMOF@P significantly inhibited tumor growth, reduced tumor weight, and prolonged survival. Moreover, Ki@MnMOF@P achieved favorable tumor accumulation without obvious systemic toxicity. Mechanistically, Ki@MnMOF@P suppressed KAT6A expression, promoted cGAMP production, enhanced cGAS expression, and increased STING phosphorylation in tumor tissues. Besides, the nanoplatform remodeled the tumor immune microenvironment by elevating IFN-β, CXCL10, TNF-α, IL-6, and IFN-γ levels and increasing CD8+ and CD4+ T-cell infiltration. These findings demonstrate that Ki@MnMOF@P integrates KAT6A inhibitor and manganese-mediated cGAS-STING activation and anti-PD-L1-mediated checkpoint blockade, providing a promising nanomedicine strategy for colorectal cancer immunotherapy.