Blocking 6PGD restricts immunosuppression driven by the innate immune response in cancer

The pentose phosphate pathway (PPP) has always been relegated to the background of cellular metabolism, but our research identifies its unique and provocative influence on cell function, specifically in myeloid-derived suppressor cells (MDSCs). We've uncovered that 6-phosphogluconate dehydrogenase (6PGD), a rate limiting enzyme in this pathway, is not just a metabolic enzyme but a crucial determinant of MDSC behavior. While the IL-6/STAT3 axis propels 6PGD activity, it also empowers MDSCs to exert their immune-suppressive prowess. When we disrupt 6PGD – either through genetic knockout or pharmacological inhibition – an astonishing transformation occurs. The accumulation of 6-phosphogluconate (6PG) sets off a cascade involving JNK1-IRS-1 interaction and PI3K-AKT-pDRP1 signaling pathway, triggering mitochondrial fragmentation and dismantling oxidative phosphorylation (OXPHOS). This change in metabolism doesn't just disrupt MDSC function; it transforms it stimulatory, leading to a strong anti-tumor response and making anti-PD1 therapies much more effective. Our results suggest we need to completely rethink the role of the PPP in cell function, with 6PGD emerging as a key target that could change the future of cancer immunotherapy. Overall design: CD45+ cells were isolated Pgdfl/fl LysmCre (KO) and Pgdfl/fl (WT) AT3 tumor bearing mice and their transcriptomics profile was evaluated by single cell RNA sequencing (scRNA-seq).