CD8A encodes the alpha subunit of CD8, an integral membrane glycoprotein essential for adaptive immunity. CD8A functions primarily as a coreceptor on cytotoxic T lymphocytes (CTLs), simultaneously engaging T-cell receptors and MHC class I peptide complexes on antigen-presenting cells [UniProt Function]. Upon binding, CD8A recruits the Src kinase LCK to the TCR-CD3 complex, initiating signaling cascades that activate CTLs to recognize and eliminate infected and tumor cells [UniProt Function]. In natural killer cells, CD8A homodimers facilitate survival and multiple target cell lysis [UniProt Function]. CD8A also promotes differentiation of activated lymphocytes into memory CD8 T cells [UniProt Function]. Clinically, CD8A expression serves as a robust biomarker for anti-tumor immunity. High CD8A expression in colorectal cancer correlates with abundant lymphocyte infiltration, PD-L1 expression, and responsiveness to pembrolizumab immunotherapy 1. Similarly, enrichment of CD8A+ tissue-resident T cells predicts responsiveness to immune checkpoint blockade in renal cell carcinoma 2. In non-small cell lung cancer treated with PD-1 inhibitors, pretreatment CD8A mRNA expression, along with signatures of CD8 T-cell activation, associates significantly with progression-free survival independent of cancer type or therapeutic agent 3. Conversely, acquired resistance to PD-(L)1 blockade involves significant decreases in intratumoral CD8a+ T cells and increased distance between tumor cells and CD8+PD-1+ T cells 4. CD8A is associated with immunodeficiency 116 [NCBI Summary].