Figure 1.

The immunoinflammatory mechanisms of CRD occurrence. TRP is metabolized in the body mainly to 5-HT and TRP. TRP generates 5-HT by the enzyme TPH, and 5-HTPDC. TRP is metabolized to KYN in response to IDO and TDO, with subsequent metabolism broadly categorized into two pathways: the TRP-KYN-3-HK-QUIN pathway located in microglia and the TRP-KYN-KYNA pathway located in astrocytes. QUIN is a potent NMDA receptor agonist that causes neuroexcitotoxicity and neurodegeneration associated with depression. Intermediate product 3-HK induces neuron cell death through oxidative stress mediated by free radicals. KYNA is the only endogenous antagonist of NMDA receptors and can attenuate QUIN-induced excitotoxicity. Cancer-induced inflammation and the excessive accumulation of pro-inflammatory cytokines (e.g., IFN-γ, IL-1β) can enhance the activity of IDO and KMO. This promotes tryptophan metabolism in favor of the TRP-KYN-3-HK-QA excitotoxic pathway, which causes an increase in QUIN and neuron cell death. Overproduction of QUIN causes an imbalance between excitotoxicity and neuro-protection, resulting in depression. Elevated QUIN also down-regulates glucocorticoid receptors, causing negative feedback dysregulation of the HPA axis, leading to an excessive release of glucocorticoids, which not only causes depression but also further activates TDO. IDO also exhibits immunosuppressive properties, reducing the number of immune cells and impairing their functions, which can facilitate cancer progression.