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Tumour-targeted nitric oxide nanotherapy overcomes sorafenib resistance and reprograms antitumour immunity in hepatocellular carcinoma

ABSTRACT: Therapeutic responses in hepatocellular carcinoma (HCC) are often limited by resistance-associated survival signaling and immune escape. Resistance to sorafenib, a first-line tyrosine kinase inhibitor (TKI) for advanced HCC, has been associated with activation of the AKT–mTOR pathway, suggesting that suppression of this axis may improve therapeutic efficacy. Here, we developed NanoNOSOR, an HCC-targeted SP94 peptide-functionalized lipid–PLGA nanoplatform for tumor-targeted, pH-responsive co-delivery of the nitric oxide donor DNIC and sorafenib. DNIC sensitized murine and human HCC cells to sorafenib by suppressing AKT–mTOR signaling. Co-loading DNIC and sorafenib into SP94-functionalized nanoparticles enhanced HCC cell uptake, promoted pH-responsive payload release, and achieved synergistic AKT–mTOR pathway suppression and cytotoxicity in vitro. In orthotopic HCC-bearing mice, NanoNOSOR preferentially accumulated in tumors and showed superior antitumor activity over single-agent nanoparticle formulations, as indicated by suppression of primary tumor growth and lung metastasis, together with increased tumor cell apoptosis. This antitumor effect was accompanied by transcriptional remodeling of the tumor microenvironment, with reduced proliferation-associated programs and increased immune-activation pathways. In addition, NanoNOSOR-mediated AKT–mTOR axis suppression downregulated PD-L1 immune checkpoint expression and enhanced intratumoral CD8⁺ T-cell infiltration and activation, linking tumor-intrinsic pathway inhibition to reduced immune escape. Biosafety analysis showed no overt hepatotoxicity, nephrotoxicity, or major organ damage. Together, these findings establish NanoNOSOR as a tumor-targeted NO–TKI co-delivery strategy that enhances therapeutic response and reprograms the HCC tumor microenvironment, providing a potential nanotherapeutic platform for overcoming therapeutic resistance in HCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE338984 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:Abstract: Cancer-associated fibroblasts (CAFs) play an important role in the induction of chemo-resistance. The objectives of this study were to clarify the mechanism underlying CAF-mediated sorafenib/lenvatinib resistance and identify a novel therapeutic target to overcome resistance to sorafenib/lenvatinib in hepatocellular carcinoma (HCC). Methods: Whole transcriptome sequencing (WTS) data of nine pairs of CAFs and para-cancer-associated fibroblasts (PAFs) were analyzed to identify key molecules that induce resistance to tyrosine kinase inhibitors (TKIs). In vitro and in vivo experiments were performed to validate selected targets and related mechanisms. Plasma secreted phosphoprotein 1 (SPP1) expression levels prior to sorafenib/lenvatinib treatment as well as progression-free survival (PFS) and overall survival (OS) of an advanced HCC cohort (n=42) were evaluated using Kaplan–Meier analysis. Results: Co-culturing CAFs and HCC cells significantly reduced the responsiveness of HCC cells to sorafenib/lenvatinib, in vitro and in vivo. Systematic integrative analysis of the WTS data of CAFs/PAFs and publicly available gene expression data indicated that CAF-derived SPP1 (CAF-SPP1) was suitable for use as a candidate molecule to induce sorafenib/lenvatinib resistance. An evaluation of the mechanisms involved indicated that CAF-SPP1 increased phosphorylation of PKCɑ, which then activated rapidly accelerated fibrosarcoma (RAF)-extracellular signal-related kinase 1/2-signal transducer and activator of transcription 3 (STAT3) and phosophoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin kinase (mTOR) in HCC cells. SPP1 inhibitors reversed CAF-induced sorafenib/lenvatinib resistance in vitro and in vivo. Patients showing high plasma SPP1 prior to sorafenib/lenvatinib treatment exhibited significantly poor PFS (P=0.005) and OS (P=0.041). Conclusions: CAF-SPP1 enhances sorafenib/lenvatinib resistance in HCC by alternatively activating oncogenic pathways via PKCɑ phosphorylation. Inhibition of CAF-SPP1 may be utilized as a therapeutic strategy against TKI resistance in HCC. Plasma SPP1 level prior to TKI treatment shows potential as a promising biomarker for predicting sorafenib/lenvatinib response in advanced HCC patients.

Project description:Introduction: Primary liver cancer remains the third leading cause of global cancer-related mortality, with hepatocellular carcinoma (HCC) constituting the predominant histological subtype. The development of malignant ascites in advanced HCC patients signifies metastatic progression and portends poor clinical outcomes, presenting a formidable therapeutic challenge.Objectives: This study aimed to engineer a natural small-molecule hydrogel for anti-tumor treatment, in order to reduce the production of ascites and achieve the dual therapeutic effect. Methods: The EP-GA hydrogel was synthesized by a one-pot method, and its morphology and mechanical properties were characterized by SEM and rheology. UHPLC-Q-Orbitrap HRMS analysis was carried out to identify the active components of EP. The assembly mechanism was analyzed by 1H-NMR and molecular dynamics. Small animal imaging techniques were utilized to evaluate the retention of EP-GA in vivo. The H22 ascites tumor model was established, and antitumor mechanism was verified by transcriptomics, metabolomics and flow cytometry.Results: The EP-GA hydrogel formed uniform nanoparticles with an average diameter of approximately 200 nm. Rheological characterization confirmed its excellent injectability. Using marker components euphol (EPH) and glycyrrhizic acid (GA) to analyze the self-assembly process, hydrogen bond interactions occurred between euphol's hydroxyl group and GA's hydrophilic domain. In H22 subcutaneous HCC xenograft models, EP-GA demonstrated significant tumor growth suppression, with a tumor growth inhibition rate (IRG) of 68.63% at the dosage of 18.75 mg/kg. Combined transcriptomic and metabolomic analysis reveals that it inhibits tumor progression by suppressing choline kinase alpha, regulating the PI3K/AKT/mTOR pathway, and inducing ROS generation and mitochondrial membrane potential decline.Conclusion: This excipient-free nanohydrogel platform effectively circumvents carrier-related toxicity while demonstrating powerful therapeutic efficacy against HCC, and this platform is a promising new strategy for HCC prevention and treatment.

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Tumour-targeted nitric oxide nanotherapy overcomes sorafenib resistance and reprograms antitumour immunity in hepatocellular carcinoma

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