CISH (cytokine-inducible SH2-containing protein) is a negative regulator of cytokine signaling that functions as a key member of the SOCS family. CISH inhibits JAK-STAT pathway signaling downstream of cytokines including IL-15, erythropoietin, prolactin, and IL-3 by suppressing STAT5 tyrosine phosphorylation 1. Mechanistically, CISH targets specific signaling proteins for proteasomal degradation; notably, it degrades ATP6V1A, a component of the V-ATPase proton pump, thereby impairing lysosomal function 2. Clinically, CISH emerges as an important therapeutic target in cancer immunotherapy. CISH knockout in natural killer cells enhances IL-15 signaling, promoting metabolic fitness and anti-tumor cytotoxicity 1. Similarly, CISH disruption in T cells using CRISPR-Cas9 increases TCR sensitivity, neoantigen recognition, and reduces PD-1 checkpoint expression by elevating FBXO38 levels 34. A phase 1 clinical trial demonstrated that adoptive transfer of neoantigen-reactive CISH-knockout tumor-infiltrating lymphocytes (TILs) in metastatic colorectal cancer patients achieved a 33% stable disease rate and one complete response in checkpoint inhibitor-refractory disease, with manageable safety 5. However, CISH upregulation in aging T cells contributes to inflammaging through lysosomal dysfunction and mitochondrial DNA release 2, indicating context-dependent effects across immune compartments.