Metabolic regulation of innate immunity in cancer immunotherapy

Innate immunity, originally recognized as the primary defense mechanism against pathogenic infections, has also been shown to have an important role in anti-tumor immunity. Host cells recognize cytosolic DNA and RNA, which triggers a cascade of signaling events via nucleic-acid sensing receptors, includ-ing endosomal Toll-like receptors (TLRs), cytoplasmic cyclic GMP-AMP synthase (cGAS) for double-stranded DNA sens-ing, and cytoplasmic retinoic acid-inducible gene I (R- IG-I) for double-stranded RNA detection. These receptors then recruit adaptor proteins, such as Toll/interleukin-1 receptor/resistance protein (TIR) domain-containing adaptor inducing interferon-β (TRIF), stimulator of interferon genes (STING), and mitochondrial antiviral signaling protein (MAVS), to acti-vate TANK-binding kinase 1 (TBK1). TBK1 phosphorylates interferon regulatory factor 3 (IRF3), leading to its dimeriza-tion and nuclear translocation, thereby initiating the expres-sion of type I interferons and inflammatory genes.