Immunometabolic characteristics of Dendritic Cells and its significant modulation by mitochondria-associated signaling in the tumor microenvironment influence cancer progression.

ABSTRACT

Dendritic cells (DCs) mediated T-cell responses is critical to anti-tumor immunity. This study explores immunometabolic attributes of DC, emphasizing on mitochondrial association, in Tumor Microenvironment (TME) that regulate cancer progression. Conventional DC subtypes cross-present tumor-associated antigens to activate lymphocytes. However, plasmacytoid DCs participate in both pro- and anti-tumor signaling where mitochondrial reactive oxygen species (mtROS) play crucial role. CTLA-4, CD-47 and other surface-receptors of DC negatively regulates T-cell. Increased glycolysis-mediated mitochondrial citrate buildup and translocation to cytosol with augmented NADPH, enhances mitochondrial fatty acid synthesis fueling DCs. Different DC subtypes and stages, exhibit variable mitochondrial content, membrane potential, structural dynamics and bioenergetic metabolism regulated by various cytokine stimulation, e.g., GM-CSF, IL-4, etc. CD8α+ cDC1s augmented oxidative phosphorylation (OXPHOS) which diminishes at advance effector stages. Glutaminolysis in mitochondria supplement energy in DCs but production of kynurenine and other oncometabolites leads to immunosuppression. Mitochondria-associated DAMPs cause activation of cGAS-STING pathway and inflammasome oligomerization stimulating DC and T cells. In this study, through a comprehensive survey and critical analysis of the latest literature, the potential of DC metabolism for more effective tumor therapy is highlighted. This underscores the need for future research to explore specific therapeutic targets and potential drug candidates.