NRF2 Engenders Anti-inflammatory Stress Macrophages

We evaluated the function of NRFhigh stress-TAMs and how they respond to immunostimulatory cues. scRNA-seq of CD45+ tumor-infiltrating leukocytes from Keap1flox/flox VavCre and WT mice (n=2 per group) revealed that macrophages were the most abundant leukocyte population in both genotypes. Differential expression, gene set enrichment analysis (GSEA), and cell-by-cell functional scoring indicated a pronounced upregulation of oxidative-stress defense and metabolic adaptation in Keap1 KO macrophages, accompanied by reduced MHC II expression, suppressed interferon-response pathways, and impaired antigen presentation capacity. Despite major shifts in oxidative stress defense and antigen presentation, key macrophage-defining functions such as phagocytic capacity remained comparable between WT and Keap1 KO TAMs. Transcription factor motif analysis further identified NRF2 as a top activated factor and STAT1 as a repressed factor in Keap1 KO TAMs. Overall design: scRNA-seq of CD45+ tumor-infiltrating leukocytes from Keap1flox/flox VavCre and WT mice (n=2 per group)