Curcumin/L-OHP co-loaded HAP for cGAS-STING pathway activation to enhance the natural immune response in colorectal cancer

Abstract

Insufficient immune cell infiltration into the tumor microenvironment (TME) greatly compromises the clinical application of immune-checkpoint inhibitors (ICIs)-based immunotherapy. Recent findings have shown that activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway can enhance natural immunity and increase lymphocyte infiltration into the TME, which presents a promising strategy for cancer immunotherapy. In this study, we constructed hydroxyapatite nanoparticles co-loaded with curcumin and L-oxaliplatin (Cur/L-OHP@HAP NPs). We analyzed the particle-size distribution, zeta potential, spectral characteristics (Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, ultraviolet-visible spectroscopy), and drug-release properties of the Cur/L-OHP@HAP NPs. The cellular uptake of the Cur/L-OHP@HAP NPs detected by flow cytometry and confocal laser-scanning microscopy. We comprehensively evaluated the anti-tumor properties and immune-activating effects of the NPs, both in vitro and in vivo. Physicochemical characterizations demonstrated that the Cur/L-OHP@HAP NPs were successfully synthesized and were capable of pH-dependent drug release. Notably, the Cur/L-OHP@HAP NPs efficiently entered cancer cells, after which the released L-OHP induced nuclear DNA (nDNA) damage to some extent. HAP promoted the release of intracellular Ca²⁺ stores in cancer cells, and curcumin inhibited Ca²⁺ efflux, resulting in intracellular Ca²⁺ overload and the release of mitochondrial DNA (mtDNA). Damage to both nDNA and mtDNA greatly stimulated the cGAS-STING pathway, thereby activating natural immunity, accompanied by immune cell recruitment to the TME. In summary, the Cur/L-OHP@HAP NPs show good prospects for improving cancer immunotherapy.

Keywords: Ca2+ overload; cGAS/STING; innate immunity; mtDNA; nDNA.