CLEC2A (keratinocyte-associated C-type lectin, KACL) is a membrane-bound C-type lectin domain family member primarily expressed on keratinocytes and dermal fibroblasts 1. It functions as a ligand for the activating NK cell receptor NKp65/KLRF2, facilitating dedicated immune recognition of keratinocytes and stimulating NK cell-mediated cytotoxicity 2. CLEC2A exists as a non-disulfide-linked homodimeric surface receptor and is alternatively spliced to produce four variants with different transmembrane domains 1. In skin immunity, CLEC2A expressed by dermal fibroblasts orchestrates crosstalk between fibroblasts and NK cells to control squamous cell carcinoma invasion 3. Loss of CLEC2A expression in cancer-associated fibroblasts compromises this immune surveillance mechanism, particularly in xeroderma pigmentosum patients 3. Beyond skin, CLEC2A has been explored therapeutically in oncolytic vaccinia virus vectors (oncoVV-CLEC2A), which suppress colorectal, lung, and hepatocellular carcinoma growth by enhancing NK cell interferon-γ production and M1-like macrophage polarization 4. CLEC2A also modulates T cell expansion [UniProt annotation]. Genetic polymorphisms in CLEC2A may influence ticagrelor pharmacokinetics 5. The keratinocyte-NKp65 axis represents a unique NKC-encoded receptor-ligand system dedicated to human skin immunobiology.