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Yuan-Jie Liu,1,2,* Shu-hong Zeng,2,3,* Wei-hua Qian,1 Min-xian Tao,1 Ying-ying Zhu,4 Jie-pin Li1– 3 1Department of Oncology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of China; 2Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China; 3No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China; 4Department of Oncology, Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang, Jiangsu, 215600, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie-pin Li, Email zjgzy027@njucm.edu.cnPurpose: Low-grade gliomas (LGG) are primary brain tumors that often affect predominantly young adults, which usually have a painless course, and have a longer survival period compared to patients with high-grade gliomas. Relatively established treatment options include surgery, radiotherapy, chemotherapy or combination therapy, as well as individualized management based on tumor location, histology, molecular features and patient characteristics. Due to the rapid development of targeted therapies, the development of new molecular targets is now a very promising research direction.Methods: We explored the diagnostic value, clinical relevance, and molecular function of deoxynucleotidyl transferase terminal-interacting proteins 2 (DNTTIP2) in LGG using MethSurv, MEXPRESS, STRING, cBioPortal, Tumor Immunity Estimation Resource (TIMER) database, Gene Expression Profiling Interactive Analysis (GEPIA) databases. Besides, the “CIBERSORT” algorithm was conducted to estimate immune cells infiltration abundance, with “ggplot2” package visualizing the results. In vivo and vitro experiments were used to verify the speculations of bioinformatics analysis.Results: In LGG patients, DNTTIP1/2 were over-expressed at mRNA levels and high DNTTIP1/2 levels correlated with poor survival in LGG patients. We confirmed that DNTTIP2 significantly promotes M2 macrophage activation and angiogenesis, which may be related to the IL6/JAK/STAT3 signaling pathway. In addition, we found that DNTTIP2 amplification was associated with an unfavorable prognosis in LGG patients. We demonstrated, finally, a correlation between DNTTIP2 gene hypermethylation and a poor prognosis in LGG.Conclusion: This study demonstrated that DNTTIP1/2 had diagnostic and prognostic value in LGG patients. The biological mechanisms of DNTTIP2 regarding angiogenesis and macrophage activation may provide new insights into the treatment of glioma.Keywords: low-grade glioma, DNTTIP2, angiogenesis, M2 macrophages infiltration, bioinformatics

Additional file 1. Table S1. Figure S1. Figure S2. Figure S3. Figure S4. Figure S5. Figure S6.