SOD2 Expression in Patients with Triple-Negative Breast Cancer is Associated with Tumor-infiltrating Lymphocytes and Prognosis

Purpose Superoxide dismutase 2 (SOD2), an antioxidant enzyme, plays a pivotal role in carcinogenesis and immune regulation. In this study, we investigated the expression and implications of superoxide dismutase (SOD2) in triple-negative breast cancer (TNBC), an aggressive subtype with varying immune profiles and clinical outcomes. Methods Multiple TNBC cohorts were analyzed with various methodologies including immunohistochemistry (IHC), proteomics, and RNA expressions. Immunostaining of SOD2 with tissue microarrays from 229 surgical samples and 144 pre-neoadjuvant chemotherapy biopsy samples were performed. 403 Formalin-fixed and paraffin-embedded samples underwent deparaffinization for protein extraction and 336 samples remained after quality control. 91 TNBC samples from The Cancer Genome Atlas data and 534 TNBC samples from public database were also analyzed. Results We identified positive correlations between SOD2 expression and immune-related genes, as well as tumor-infiltrating lymphocytes (TILs) levels, while observing negative associations with fibrosis related pathways. Immunohistochemical analysis further supported the positive correlation between SOD2 and immune response. Furthermore, elevated SOD2 expression predicted favorable survival outcomes in patients with TNBC. Notably, analysis of single-cell RNA-seq data revealed increased SOD2 expression in cancer-associated fibroblasts associated with higher TILs levels, enhanced inflammatory signaling, and reduced fibrogenesis. Conclusion High SOD2 expression in TNBC is associated with improved outcomes and heightened immune responses, underscoring its potential as a modulator of the tumor microenvironment.