6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells

TL;DR

This study shows that blocking 6PGD, an enzyme in the pentose phosphate pathway, disrupts the function of tumor-associated immune cells and improves cancer immunotherapy.

Contribution

The study identifies 6PGD as a novel metabolic regulator of M-MDSCs and a potential therapeutic target in cancer immunotherapy.

Findings

6PGD inhibition impairs M-MDSC immunosuppressive function and suppresses tumor growth.

Blocking 6PGD leads to mitochondrial fragmentation and a shift toward a proinflammatory M1-like phenotype in M-MDSCs.

6PGD blockade synergizes with anti-PD-1 immunotherapy to improve therapeutic outcomes in a preclinical model.

Abstract

The mechanisms underlying the metabolic adaptation of myeloid cells within the tumor microenvironment remain incompletely understood. Here, we identify 6-phosphogluconate dehydrogenase (6PGD), a rate-limiting enzyme in the pentose phosphate pathway (PPP), as an important regulator of monocytic-myeloid derived suppressor cell (M-MDSC) function. Our findings reveal that tumor M-MDSCs upregulate 6PGD expression via IL-6/STAT3 signaling. Blocking 6PGD, using either genetic or pharmacological approaches, impairs the immunosuppressive function of M-MDSCs and suppresses tumor growth. Mechanistically, 6PGD inhibition leads to the accumulation of its substrate, 6-phosphogluconate (6PG), within M-MDSCs, activates the JNK1-IRS1 and PI3K-AKT-pDRP1 signaling pathways, leading to mitochondrial fragmentation and elevated mitochondrial reactive oxygen species (ROS). This metabolic shift drives M-MDSCs toward an M1-like proinflammatory phenotype. Furthermore, 6PGD blockade synergizes with anti-PD-1 immunotherapy in a preclinical tumor model, substantially improving therapeutic outcomes. Our data reveals 6PGD as a possible therapeutic target to disrupt M-MDSC function and improve cancer immunotherapy outcomes.

Myeloid derived suppressor cells (MDSC) use different metabolic mechanisms to adapt to the tumour microenvironment. Here the authors show that 6-phosphogluconate dehydrogenase (6PGD) is important for MSDC function and that blockade of 6PGD impaired MDSC function and suppresses tumour growth leading to metabolic and functional changes in the MDSC and a more pro-inflammatory phenotype.

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