Pan-Cancer Landscape of NEIL3 in Tumor Microenvironment: A Promising Predictor for Chemotherapy and Immunotherapy

SIMPLE SUMMARY: A reliable efficacy predictor for immunotherapy is warranted due to its unsatisfying responsive rate among cancer patients. Endonuclease VIII-like protein 3 (NEIL3) is a DNA glycosylase reported to be heightened in specific cancers. However, little is known regarding the immunological features of NEIL3 among cancers. Here, a pan-cancer landscape was presented to elucidate the characteristics of NEIL3 in the tumor microenvironment (TME). In this study, we demonstrated that NEIL3 may be a promising indicator for tumor prognosis, immunotherapy, and chemotherapy. ABSTRACT: With the aim of enhancing the understanding of NEIL3 in prognosis prediction and therapy administration, we conducted a pan-cancer landscape analysis on NEIL3. The mutation characteristics, survival patterns, and immune features of NEIL3 across cancers were analyzed. Western blotting, qPCR, and immunohistochemistry were conducted to validate the bioinformatics results. The correlation between NEIL3 and chemotherapeutic drugs, as well as immunotherapies, was estimated. NEIL3 was identified as an oncogene with prognostic value in predicting clinical outcomes in multiple cancers. Combined with the neoantigen, tumor mutational burden (TMB), and microsatellite instability (MSI) results, a strong relationship between NEIL3 and the TME was observed. NEIL3 was demonstrated to be closely associated with multiple immune parameters, including infiltrating immunocytes and pro-inflammatory chemokines, which was verified by experiments. More importantly, patients with a higher expression of NEIL3 were revealed to be more sensitive to chemotherapeutic regimens and immune checkpoint inhibitors in selected cancers, implying that NEIL3 may be an indicator for therapeutic administration. Our study indicated NEIL3 has a strong association with the immune microenvironment and phenotypic changes in certain types of cancers, which facilitated the improved understanding of NEIL3 across cancers and highlighted the potential for clinical application of NEIL3 in precision medical stratification.