Targeted Deletion of Peroxiredoxin 1 Enhances Anti-Tumor Immunity in Colorectal Cancer by Reprogramming the Immunosuppressive Tumor-Associated Macrophages.

Peroxiredoxin 1 (PRDX1) overexpression in colorectal cancer (CRC) correlates with poor prognosis and reduced T-cell infiltration. However, the mechanism underlying PRDX1-mediated immune suppression remains elusive. In this study, we found that knockout of PRDX1 robustly suppressed AOM/DSS-induced colonic adenocarcinoma compared with wild-type C57BL/6J mice, accompanied by highly infiltrated CD4/CD8T cells and reduced CD163 tumor-associated macrophages (TAMs). Furthermore, PRDX1 knockdown in CRC cells inhibited M2 macrophage polarization by impairing hypoxia-inducible factor 1α (HIF-1α)/GLUT-1-mediated glycolysis and lactate secretion. Mechanistically, PRDX1 binds to Cullin-2 as a molecular chaperone, thereby suppressing ubiquitination and degradation of HIF-1α. The PRDX1 mutant abolished the ability to bind to Cullin-2, suggesting that Cys83 is an active site of PRDX1 in regulating HIF-1α/GLUT-1-mediated glycolysis. Importantly, PRDX1 deletion in macrophages reversed the immunosuppressive phenotype and reciprocally enhanced the phagocytosis, inhibited CRC cell growth and migration. Cytokine assay demonstrated that PRDX1 deficiency increased IL-1β and TNF-α secretion by activating the JAK/STAT1/NF-κB pathway, promoting M1 macrophage polarization. Notably, PRDX1 knockout macrophages inhibited syngeneic tumor growth and enhanced sensitivity to anti-PD-1 therapy in vivo. In conclusion, targeted deletion of PRDX1 enhances anti-tumor immunity in CRC by reprogramming the immunosuppressive TAMs, revealing a novel role of PRDX1 as a potential drug target during anti-tumor immunotherapy.