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

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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.

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