IDO2 (indoleamine 2,3-dioxygenase 2) is an enzyme that catalyzes the first step of tryptophan catabolism via the kynurenine pathway, though it exhibits extremely low catalytic activity compared to its paralog IDO1 1. Despite its poor enzymatic function, IDO2 appears to function primarily as a signaling molecule rather than a metabolic enzyme 1. The protein plays important roles in immune regulation and autoimmune responses, with IDO2 deletion in mice leading to defects in allergic and autoimmune responses and impaired IDO1-mediated T regulatory cell generation 2. In cancer contexts, IDO2 shows variable effects depending on tumor type - it acts protectively in pancreatic ductal adenocarcinoma (PDAC) where genetic loss decreases tumor development 3, but may increase risk in non-small cell lung cancer 4. Two prevalent inactivating single nucleotide polymorphisms (SNPs) in humans provide natural loss-of-function variants, with biallelic carriers showing improved survival with adjuvant radiotherapy in PDAC 3. The evolutionary persistence of IDO2 across species despite minimal enzymatic activity suggests important biological functions beyond tryptophan metabolism 1, positioning it as a potential therapeutic target in cancer immunotherapy 5.