Targeting NCAPG with Arundanine Suppresses Neutrophil/NET-Mediated Immune Evasion and Enhances CD8⁺ T Cell Function in Lung Squamous Cell Carcinoma.
- 1Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China.
- 2Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China.
Abstract
Non-SMC condensin I complex subunit G (NCAPG) is implicated in tumor progression and TGF-β pathway activation, yet its roles in oncogenesis and immune modulation within the lung squamous cell carcinoma (LUSC) microenvironment remain largely unexplored. Here, we used bioinformatics analysis to identify key upregulated genes in LUSC and assessed the effects of NCAPG and its upstream regulator E2F transcription factor 8 (E2F8) on malignant phenotypes via gain- and loss-of-function assays in NCI-H226 and NCI-H1703 LUSC cell lines, with in vivo efficacy validated using KLN205 cell isografts and NTCU-induced primary LUSC mouse models. Neutrophil polarization, neutrophil extracellular trap (NET) formation, and CD8⁺ T cell cytotoxicity was analyzed in co-culture systems and tumor tissues. Arundanine was identified as a potential NCAPG inhibitor via molecular docking and tested as monotherapy or in combination with anti-PD-1 therapy. We found that NCAPG was significantly upregulated in LUSC, and NCAPG depletion markedly impaired LUSC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, NCAPG activated TGF-β signaling, which drove pro-tumor N2 neutrophil polarization and induced NETosis; these NETs upregulated PD-L1 expression on tumor cells and suppressed the expansion and cytotoxic function of CD8⁺ T cells. E2F8 was found to transcriptionally activate NCAPG by directly binding to its promoter. Furthermore, Arundanine destabilized NCAPG protein, suppressed TGF-β-mediated NET formation, and potentiated anti-PD-1 therapy to significantly prolong survival in LUSC models. Collectively, the E2F8/NCAPG axis promotes LUSC progression by orchestrating a TGF-β-driven immunosuppressive microenvironment, and targeting NCAPG with Arundanine represents a promising therapeutic strategy to overcome immune evasion and sensitize LUSC to PD-1 blockade.
Related
- MYC Suppresses Mitochondrial Function in Hepatocellular Carcinoma through NRF1-Driven Receptor-Mediated Mitophagy
- Dual targeting of ACSS2 and ACLY by a novel inhibitor S8588 suppresses oncogenic lipogenesis and overcomes metabolic compensation in oral squamous cell carcinoma
- DCTN2 inhibited cellular senescence through targeting TRIM21 mediated MST2 ubiquitination and activation in hepatocellular carcinoma.
- Targeting asparagine synthetase triggers ferroptosis and suppresses endometrial cancer growth via Atractylenolide II
- Pharmacologically Targeting DHODH-Dependent Pyrimidine Metabolism with HSA-Conjugated BRQ Suppresses Leukemogenesis
BibTeX
@article{gu2026targeting,
title = {{Targeting NCAPG with Arundanine Suppresses Neutrophil/NET-Mediated Immune Evasion and Enhances CD8⁺ T Cell Function in Lung Squamous Cell Carcinoma.}},
author = {Xuyu Gu and Dongning Lu and Ming Deng and Tao Ge and Kaiqi Jin and Xinnan Xu and Li Xu},
journal = {International journal of biological sciences},
year = {2026},
month = sep,
doi = {10.7150/ijbs.134668},
url = {https://europepmc.org/article/MED/42909913},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting NCAPG with Arundanine Suppresses Neutrophil/NET-Mediated Immune Evasion and Enhances CD8⁺ T Cell Function in Lung Squamous Cell Carcinoma.
AU - Xuyu Gu
AU - Dongning Lu
AU - Ming Deng
AU - Tao Ge
AU - Kaiqi Jin
AU - Xinnan Xu
AU - Li Xu
PY - 2026
DA - 2026/09/11
JO - International journal of biological sciences
DO - 10.7150/ijbs.134668
UR - https://europepmc.org/article/MED/42909913
AB - Non-SMC condensin I complex subunit G (NCAPG) is implicated in tumor progression and TGF-β pathway activation, yet its roles in oncogenesis and immune modulation within the lung squamous cell carcinoma (LUSC) microenvironment remain largely unexplored. Here, we used bioinformatics analysis to identify key upregulated genes in LUSC and assessed the effects of NCAPG and its upstream regulator E2F transcription factor 8 (E2F8) on malignant phenotypes via gain- and loss-of-function assays in NCI-H226 and NCI-H1703 LUSC cell lines, with in vivo efficacy validated using KLN205 cell isografts and NTCU-induced primary LUSC mouse models. Neutrophil polarization, neutrophil extracellular trap (NET) formation, and CD8⁺ T cell cytotoxicity was analyzed in co-culture systems and tumor tissues. Arundanine was identified as a potential NCAPG inhibitor via molecular docking and tested as monotherapy or in combination with anti-PD-1 therapy. We found that NCAPG was significantly upregulated in LUSC, and NCAPG depletion markedly impaired LUSC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, NCAPG activated TGF-β signaling, which drove pro-tumor N2 neutrophil polarization and induced NETosis; these NETs upregulated PD-L1 expression on tumor cells and suppressed the expansion and cytotoxic function of CD8⁺ T cells. E2F8 was found to transcriptionally activate NCAPG by directly binding to its promoter. Furthermore, Arundanine destabilized NCAPG protein, suppressed TGF-β-mediated NET formation, and potentiated anti-PD-1 therapy to significantly prolong survival in LUSC models. Collectively, the E2F8/NCAPG axis promotes LUSC progression by orchestrating a TGF-β-driven immunosuppressive microenvironment, and targeting NCAPG with Arundanine represents a promising therapeutic strategy to overcome immune evasion and sensitize LUSC to PD-1 blockade.
SN - 1449-2288
ER -