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

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.