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  3. Targeting G-quadruplex by TMPyP4 for inhibition of colorectal cancer through cell cycle arrest and boosting anti-tumor immunity

Targeting G-quadruplex by TMPyP4 for inhibition of colorectal cancer through cell cycle arrest and boosting anti-tumor immunity

  • Cell Death Dis. 2024 Nov 11;15(11):816. doi: 10.1038/s41419-024-07215-2.
Peisi Li # 1 2,  Dawang Zhou # 3,  Yumo Xie # 1 2,  Ze Yuan 1 2,  Mingzhe Huang 1 2,  Gaopo Xu 1 2,  Junfeng Huang 1 2,  Zhuokai Zhuang 1 2,  Yanxin Luo 4 5 6,  Huichuan Yu 7 8,  Xiaolin Wang 9 10
Affiliations

Affiliations

  • 1 Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Department of Hepatobiliary and Pancreatic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.
  • 4 Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. luoyx25@mail.sysu.edu.cn.
  • 5 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. luoyx25@mail.sysu.edu.cn.
  • 6 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. luoyx25@mail.sysu.edu.cn.
  • 7 Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. yuhch5@mail.sysu.edu.cn.
  • 8 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. yuhch5@mail.sysu.edu.cn.
  • 9 Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. wangxlin3@mail.sysu.edu.cn.
  • 10 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. wangxlin3@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 39528472 DOI: 10.1038/s41419-024-07215-2
Abstract

G-quadruplex (G4) is a noncanonical DNA secondary structure known to induce DNA damage and regulate the expression of immune-related genes. We aim to exploit the G4 folding as a treatment strategy to trigger anti-tumor immune response. In this study, we observe that the abundant genomic G4 in epithelial cells coexists with increased infiltration of CD8+ T cells in colorectal Cancer tissue. Furthermore, our data substantiate the inhibitory effect of the G4 ligand TMPyP4 on Cancer progression while concurrently stimulating anti-tumor immunity. Mechanistically, TMPyP4 impedes Cancer cell proliferation and induces G2/M cell cycle arrest. Additionally, in vivo experiments demonstrate that TMPyP4 enhances the anti-tumor immune response by triggering DNA damage and activating the cGAS-STING pathway, which fosters CD8+ T cell activation and dendritic cell maturation. Importantly, the combined treatment of TMPyP4 and anti-PD1 exhibits a synergistic therapeutic effect on colorectal Cancer. In summary, our findings underscore the potential of the G4 ligand TMPyP4 as a dual strategy to target colorectal cancer: inhibiting Cancer progression and augmenting anti-tumor immunity through the activation of cGAS-STING pathway.

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