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

• Published in: Cell death & disease 2024-11, Vol.15 (11), p.816-10, Article 816
• Main Authors: Li, Peisi, Zhou, Dawang, Xie, Yumo, Yuan, Ze, Huang, Mingzhe, Xu, Gaopo, Huang, Junfeng, Zhuang, Zhuokai, Luo, Yanxin, Yu, Huichuan, Wang, Xiaolin
• Format: Article
• Language: English
• Subjects: 13; 13/31; 13/51; 38/77; 38/90; 38/91; 631/67/1059; 631/67/327; 64/60; 96/2; 96/31; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cancer; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell Biology; Cell Culture; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Dendritic cells; DNA damage; DNA structure; Epithelial cells; G-Quadruplexes - drug effects; Humans; Immunity; Immunity (Disease); Immunology; Infiltration; Life Sciences; Ligands; Lymphocytes; Lymphocytes T; Membrane Proteins - metabolism; Metastases; Mice; Nucleotidyltransferases - metabolism; PD-1 protein; Porphyrins - pharmacology; Protein structure; Secondary structure; Signal Transduction - drug effects; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-07215-2

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. Highlights The tissue region with abundant G4 in epithelial cells exhibits more infiltration of CD8 + T cells in colorectal cancer. The G4 ligand TMPyP4 inhibits cancer cell proliferation by inducing a G2/M cell cycle arrest. The G4 ligand TMPyP4 promotes the activation of CD8 + T cells and the maturation of DCs by activating the cGAS-STING pathway.