Cytokine-inducible SH2 domain-containing protein (CISH) (CISH)

Cytokine-inducible SH2 domain-containing protein (CISH) is a member of the suppressor of cytokine signaling (SOCS) family that serves as a critical intracellular checkpoint in Natural Killer (NK) cells (UniProt Q9NSE2). It primarily functions by negatively regulating interleukin-15 (IL-15) signaling through the inhibition of Janus kinase (JAK) activity and subsequent STAT5 phosphorylation (Delconte et al., 2016, Nature Immunology). By targeting phosphorylated JAK1 for proteasomal degradation, CISH limits the activation, proliferation, and survival of NK cells, effectively acting as a brake on the innate immune response. In the context of oncology, CISH is highly induced upon NK cell activation and its expression is associated with NK cell exhaustion in the tumor microenvironment (Daussy et al., 2020, JEM). Therapeutic strategies, particularly CRISPR-Cas9 gene editing in adoptive cell therapies like CAR-NK cells, aim to delete CISH to enhance the metabolic fitness and cytotoxic potential of these cells against various malignancies (NCT04426669). Research indicates that CISH-deficient NK cells exhibit superior control of primary tumor growth and metastasis in preclinical models by maintaining high levels of effector function.

Other names

CISSOCSG18BACTS2Suppressor of cytokine signalingCytokine-inducible SH2 protein

Inhibition or genetic deletion of CISH prevents the negative regulation of interleukin-15 (IL-15) signaling, thereby enhancing the metabolic fitness, survival, and cytotoxic activity of Natural Killer (NK) cells against tumor cells.