NOX4 Modulates Breast Cancer Progression Through Cancer Cell Metabolic Reprogramming and CD8 + T Cell Antitumor Activity

Yingying Xiong ¹ Yiming Weng ² Shan Zhu ² Jian Qin ² Jia Feng ² Xiaopeng Jing ¹ Chao Luo ³ Gong Wei ⁴ Rui Sun ^2* Min Peng ^2*

• ¹ Department of Clinical laboratory, Wuhan Fourth Hospital, Wuhan 430033, China., wuhan, China
• ² Renmin Hospital of Wuhan University, Wuhan, China
• ³ Department of Central Laboratory, The Affiliated Huaian No.1 People's Hospital, Nanjing Medical University, huaian, China
• ⁴ Department of Oncology, XiangYang Central Hospital, Hubei University of Arts and Science, Xiangyang, China

NOX4 in breast cancer exerts complex effects on tumor growth, metabolism, and immune response. Using CRISPR-Cas9 technology, we performed NOX4 knockout in breast cancer models to delineate its role in tumor biology. NOX4 knockout led to enhanced tumor growth, highlighting its oncogenic potential. The loss of NOX4 activated the Myc signaling pathway, with its absence leading to compensatory oncogenic signaling. Metabolic profiling of NOX4-deficient cells revealed upregulation of glycolysis and fatty acid oxidation (FAO), indicating a metabolic reprogramming that promotes cell growth and survival. Myc emerged as a crucial effector in driving the malignancy of NOX4-deficient cells, suggesting therapeutic potential in targeting the NOX4-Myc axis. Additionally, NOX4 enhanced the antitumor activity of CD8 + T cells, suggesting a role in modulating immune responses and the tumor microenvironment. Overexpression of NOX4 correlated with improved prognosis and enhanced tumor immunotherapy efficacy, underscoring its potential as a biomarker for clinical outcomes and as a target for immunotherapeutic enhancement. NOX4 plays a dual role in breast cancer, impacting tumor growth, metabolism, and immune response. Targeting the NOX4-Myc signaling pathway and modulating NOX4 expression offers promising therapeutic strategies for improving breast cancer treatment outcomes. This study emphasizes the need for a nuanced understanding of NOX4's role in breast cancer to develop effective therapies.