Cish, also known as cytokine-inducible SH2-containing protein, is a key negative regulator in multiple cytokine signaling pathways. It belongs to the suppressor of cytokine signaling (SOCS) family. Cish plays important roles in immunity, erythropoiesis, and the regulation of cell metabolism, lysosomal function, and cell activation. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, have been crucial for studying its functions [1,2,3,4,5,6,7,8,9].

In human iPSC-derived NK cells, deletion of CISH promotes metabolic reprograming, enhancing in vivo persistence and anti-tumor activity through increased IL-15-mediated JAK-STAT signaling and improved metabolic fitness [1]. In T cells from older adults, increased CISH expression impairs lysosomal function, leading to mitochondrial DNA release and inflammaging [2]. Cish knockout mice showed altered hematopoietic responses but similar outcomes to malaria infection [3]. Targeting CISH in NK cells enhances natural cytotoxicity receptor signaling, reduces NK cell exhaustion, and improves solid tumor immunity [4]. During DC development, CISH knockdown affects the expression of key molecules, DC yield, and CTL activation [5]. In alveolar macrophages, Cish deficiency leads to phenotypic changes associated with enhanced cytokine signaling [6]. In ILC2s, global or conditional CISH deficiency increases cell expansion and activation, affecting mucosal immunity [7]. In lung fibroblasts, CISH negatively regulates IL-13-induced CCL26 production related to eosinophilic inflammation in asthma [8]. In mice infected with Mycobacterium tuberculosis, CISH controls bacterial burden early after infection via innate immune mechanisms [9].

In conclusion, Cish acts as a negative regulator in multiple biological processes, including cytokine signaling, cell metabolism, and lysosomal function. KO and CKO mouse models have revealed its roles in various disease-related conditions, such as cancer, aging-related inflammation, malaria, solid tumor immunity, asthma, and tuberculosis. These findings contribute to understanding the underlying mechanisms of these diseases and may provide potential therapeutic targets.