Citation: Yuantao Mao, Wen Zhang, Xinru Qi, Chuanchen Wu, Xin Wang, Ping Li, Bo Tang. Dual-channel and HSCs-targeted fluorescent nanoprobes illuminate the COX-2-O₂^•−/NO-Pten axis driving fibrosis-induced hepatocellular carcinoma immune evasion[J]. Chinese Chemical Letters, ;2026, 37(12): 112314. doi: 10.1016/j.cclet.2025.112314 shu

Dual-channel and HSCs-targeted fluorescent nanoprobes illuminate the COX-2-O₂^•−/NO-Pten axis driving fibrosis-induced hepatocellular carcinoma immune evasion

Yuantao Mao ^a ,
Wen Zhang ^{a, *,} ,
Xinru Qi ^a ,
Chuanchen Wu ^d ,
Xin Wang ^a ,
Ping Li ^{a, b, *,} ,
Bo Tang ^{a, c}

a.
College of Chemistry, Chemical Engineering, and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Ji'nan 250014, China
b.
College of Chemistry and Chemical Engineering, Key Laboratory of Water Security and Water Environment Protection in Plateau Intersection, Ministry of Education, Northwest Normal University, Lanzhou 730070, China
c.
Laoshan Laboratory, Qingdao 266237, China
d.
College of Medicine, Linyi University, Linyi 276000, China

zhangwen@sdnu.edu.cn

lip@sdnu.edu.cn

Received Date: 2 September 2025
Revised Date: 18 December 2025
Accepted Date: 22 December 2025
Available Online: 23 December 2025

Figures(4)

Hepatic fibrosis (HF) is critical for immune evasion in hepatocellular carcinoma (HCC), mainly driven by hepatic stellate cell (HSCs) activation, though the underlying molecular mechanisms linking HSCs activation to immune evasion remain unclear. Here, we report a targeted fluorescent nanoprobe platform for visualizing and dissecting oxidative stress dynamics driving HCC immune evasion in fibrotic tumor microenvironments. We develop a dual-channel fluorescent probe (FP-CP) enabling crosstalk-free detection of superoxide anion (O₂^•−) and nitric oxide (NO) with high sensitivity and spectral separation. To achieve HSCs-specific targeting, FP-CP is encapsulated into nanoparticles surface-functionalized with the HSCs-targeting peptide HTP, yielding HTP-FP-CP nanoprobes that selectively accumulate in fibrotic niches. Using this nanoplatform, in situ imaging reveals coordinated O₂^•−/NO elevation during HSCs activation, directly linked to oxidative inactivation of the tumor suppressor phosphatase and tensin homolog (Pten). Mechanistically, cyclooxygenase-2 (COX-2) elevation drives O₂^•−/NO accumulation, with O₂^•− and their products peroxynitrite (ONOO⁻) directly oxidizing/nitrifying residues in Pten. This oxidative-mediated Pten suppression activates the protein kinase B (AKT)- mammalian target of rapamycin (mTOR)-programmed cell death ligand 1 (PD-L1) axis, facilitating HCC immune evasion. Our study identifies the COX-2-O₂^•−/NO-Pten-Akt-mTOR-PD-L1 pathway as a critical oxidative stress-mediated molecular bridge between HF and HCC, and establishes HTP-FP-CP as a powerful nanoplatform for probing these oxidative stress dynamics in vivo, providing insights into potential therapeutic strategies for intercepting HCC in fibrotic patients.
- Antitumor agents,
- Nanoparticles,
- 6-Aminonicotinamide,
- Disulfidptosis,
- Ovarian cancer therapy
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通讯作者: 陈斌, bchen63@163.com

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沈阳化工大学材料科学与工程学院沈阳 110142

Dual-channel and HSCs-targeted fluorescent nanoprobes illuminate the COX-2-O2•−/NO-Pten axis driving fibrosis-induced hepatocellular carcinoma immune evasion

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通讯作者: 陈斌, bchen63@163.com

Dual-channel and HSCs-targeted fluorescent nanoprobes illuminate the COX-2-O₂^•−/NO-Pten axis driving fibrosis-induced hepatocellular carcinoma immune evasion