HCST (hematopoietic cell signal transducer) is a transmembrane adapter protein that associates with KLRK1 to form an activation receptor critical for immune surveillance. The KLRK1-HCST complex recognizes stress-induced ligands (MICA, MICB, and ULBPs) upregulated during viral infection and tumor transformation, triggering cytotoxicity in natural killer and T cells [UniProt]. Upon ligand engagement, HCST functions as a docking site for PI3K and GRB2, activating downstream signaling cascades including PI3K, MAP2K/ERK, and JAK2/STAT5 pathways essential for target cell killing [UniProt]. In NK cells, KLRK1-HCST signaling directly induces cytotoxicity and enhances cytokine production, while in T cells it provides costimulation for TCR-induced activation [UniProt]. Clinically, HCST expression serves as a prognostic biomarker in clear cell renal cell carcinoma, where high expression correlates with advanced tumor stage, poor overall survival, and increased tumor-infiltrating immune cells including dendritic cells 1. Additionally, HCST represents a novel predictive biomarker for immunotherapy response in non-small cell lung cancer, with superior predictive ability compared to PD-L1 2. Recent therapeutic applications include engineering hiPSC-derived NK cells expressing HCST-NKG2D complex to enhance anti-tumor activity against solid tumors 3.