LSI312A Modulates Myeloid-derived Suppressor Cell-Mediated Immunosuppression via NLRP3 Inflammasome Inhibition.

Myeloid-derived suppressor cells (MDSCs) are immune suppressive cells that inhibit neighboring immune cells activity and promote tumor growth by producing anti-inflammatory mediators such as nitric oxide (NO), reactive oxygen species (ROS), and cytokines. They also induce pro-inflammatory cytokines like IL-1β, further enhancing immunosuppression and resistance to therapy. The NLRP3 inflammasome plays a crucial role in host defense against infections but also contributes to autoimmune diseases and cancer when dysregulated. Due to its role in inflammation and cancer, the NLRP3 inflammasome is a potential therapeutic target. Here, we demonstrate that LSI312A, a biosynthetic compound of Homoisoflavanoids, inhibits NLRP3-mediated inflammasome activation in MDSCs. LSI312A downregulated pro-caspase-1, and pro-IL-1β in the Toll-like receptor 4 (TLR4)-induced NLRP3 inflammasome pathway. It also reduced NO production and IL-1β secretion. In an acute bacterial infection mouse model, LSI312A depleted MDSCs by inhibiting NLRP3 inflammasome activation, while sparing other immune cells. These findings suggest that LSI312A modulates MDSC-mediated immunosuppression and highlights its potential as an adjuvant therapy for cancer treatment.