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

## TL;DR

Deleting PRDX1 in colorectal cancer improves anti-tumor immunity by changing harmful macrophages into helpful ones.

## Contribution

This study identifies PRDX1 as a new drug target in colorectal cancer by showing how its deletion reprograms immunosuppressive macrophages.

## Key findings

- PRDX1 knockout in mice reduced tumor growth and increased T-cell infiltration while decreasing immunosuppressive macrophages.
- PRDX1 deletion in macrophages promotes M1 polarization and enhances anti-tumor immunity via increased IL-1β and TNF-α secretion.
- Targeting PRDX1 improves response to anti-PD-1 immunotherapy in colorectal cancer models.

## Abstract

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+/CD8+ T 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 PRDX1Cys83Ser 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.

This study reveals a dual mechanism by which PRDX1 knockdown alleviates immunosuppression in CRC. On the one hand, PRDX1 knockdown in CRC cells inhibits M2 macrophage polarization by destabilizing HIF‐1α through impaired binding to Cullin‐2, thereby suppressing GLUT‐1‐dependent glycolysis and lactate secretion. On the other hand, loss of PRDX1 in macrophages restrains M2 polarization and enhances T‐cell‐mediated anti‐tumor immunity by promoting the secretion of inflammatory factors (IL‐1β and TNFα) via activation of JAK‐STAT1/NF‐κB signaling pathways. These results underscore the therapeutic potential of targeting PRDX1 to reverse immunosuppression and enhance anti‐tumor immunity in CRC.