Gold Nanorod-Based USP8 Inhibition Combined with Photothermal Therapy Enhances Antitumor Efficacy in Gastric Cancer.

Abstract

BACKGROUND: Gastric cancer (GC) remains a major global malignancy with limited therapeutic options for advanced disease. Ubiquitin-specific peptidase 8 (USP8) is a deubiquitinating enzyme involved in tumor progression and immune regulation, but its therapeutic potential in GC remains incompletely explored. METHODS: Public multi-omics data, including The Cancer Genome Atlas (TCGA), The Cancer Dependency Map (DepMap), single-cell transcriptomic, spatial transcriptomic, and immune-infiltration analyses, were used to investigate the biological relevance of USP8 in GC. A gold nanorod (GNR)-based nanoplatform coated with silicon dioxide (SiO₂) and loaded with the USP8 inhibitor DUB-IN-2 was constructed and designated GNR@SiO2-USP8i. The physicochemical properties, drug loading, release behavior, photothermal performance, cellular uptake, cytotoxicity, reactive oxygen species (ROS) generation, deoxyribonucleic acid (DNA) damage, and in vivo antitumor efficacy were evaluated. RESULTS: USP8 was upregulated in GC and preferentially enriched in malignant cells. DepMap and experimental validation showed that USP8 contributed to GC cell proliferation. Immune analyses suggested that high USP8 expression was associated with reduced CD8⁺ T-cell infiltration and altered C-X-C motif chemokine ligand 12 (CXCL12)-C-X-C motif chemokine receptor 4 (CXCR4) signaling. Further experiments showed that USP8 manipulation was accompanied by concordant changes in protein kinase B (AKT) phosphorylation and CXCL12 expression and influenced Jurkat cell chemotaxis. GNR@SiO2-USP8i exhibited effective DUB-IN-2 loading, near-infrared (NIR)-responsive release, and favorable photothermal performance. Upon NIR irradiation, GNR@SiO2-USP8i markedly reduced GC cell viability, increased ROS generation and DNA damage, and suppressed tumor growth in vivo. CONCLUSION: GNR@SiO2-USP8i integrates USP8 inhibition with NIR-triggered photothermal therapy and demonstrates enhanced antitumor activity in GC, supporting further investigation of USP8-targeted nanotherapeutic strategies.

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