Systematic regulation of immune checkpoint molecules by redox regulators CNC-bZIP transcription factors

Although oxidative stress is strongly connected to the initiation and progression of cancer, the underlying molecular pathways remain unknown. The redox regulator CNC-bZIPs are important transcription factor groups that mediate the interplay of environmental cues and intercellular homeostasis. Immune checkpoint molecules (ICMs) are key molecules that mediate the communication between immune cells and tumor cells. This research sought to explore the transcriptional regulatory effects of CNC-bZIPs on ICMs.

The potential role of CNC-bZIPs in tumors and the correlation between CNC-bZIPs and ICMs were analyzed by the gene expression characteristics, survival analysis, and correlation analysis in TCGA data. And the transcriptional regulatory effects of CNC-bZIPs on ICMs were verified through cis acting element analysis and promoter activity reporter experiments.

In this study, we found that high expression of CNC-bZIPs predicted poor prognosis, and we determined that CNC-bZIPs are universally connected to ICMs by analyzing gene expression correlation in TCGA tumor data. Specifically, CD47 and CD274 exhibit universally positive correlation with CNC-bZIPs in various tumor tissues. Promoter analysis revealed that there are several ARE elements, which are specifically recognized by CNC-bZIPs, in the promoter regions of CD47 and CD274 genes. Overexpression of NFE2L1 and NFE2L2 was used to explore the regulation of common ICM genes, such as CD47 and CD274, and the transcriptional regulatory effect of CNC-bZIPs on ICMs was confirmed using promoter activity reporter experiments.

In this study, the universal and systematic transcriptional regulatory role of the CNC-bZIP transcription factor family on ICMs was discovered. According to this study, the results and conclusions drawn are based on gene expression correlation and promoter activity assays, the CNC-bZIPs/ICMs transcriptional regulatory axis was revealed to be a potential regulatory axis that may drive redox signaling and anti-tumor immune responses.