CISH, a key intracellular checkpoint, in comparison and combination to existing and emerging cancer immune checkpoints.

ABSTRACT: Over the past decade, Immuno-Oncology has largely focused on blocking inhibitory surface receptors like PD-1 to enhance T cell anti-tumor activity. However, intracellular immune checkpoints such as CISH, which function independently of tumor-expressed ligands, offer powerful and previously untapped therapeutic potential. As a downstream regulator of TCR signaling, CISH controls T cell activation, expansion, and neoantigen reactivity. Though historically considered undruggable, recent advances in CRISPR engineering have enabled functional interrogation of these targets. We demonstrate that CISH deletion enhances T cell activation and anti-cancer functions more effectively than other emerging intracellular checkpoints. In CAR-T cells, CISH inactivation significantly increased sensitivity to

SUBMITTER: Cano F 

PROVIDER: S-EPMC12936186 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature