LRCH1 (leucine-rich repeats and calponin homology domain containing 1) functions as a negative regulator of immune cell migration and cytotoxicity through multiple molecular mechanisms. LRCH1 directly binds the linker for activation of T cells (LAT) and reduces its phosphorylation and interaction with GRB2, thereby suppressing T cell receptor signaling 1. Additionally, LRCH1 competes with Cdc42 for interaction with guanine-nucleotide exchange factor DOCK8, preventing PKCα-induced DOCK8 activation and CD4+ T cell migration in response to chemokine stimulation 2. LRCH1 similarly inhibits NK cell cytotoxicity by attenuating Src kinase signaling 3. Clinically, LRCH1 loss-of-function enhances protective immunity: Lrch1-deficient mice show improved CD8+ T cell responses to influenza and Listeria, with enhanced tumor clearance in B16 melanoma models 1. LRCH1 knockout in CAR T cells targeting glypican-3 improves migration and proliferation, suggesting therapeutic potential 1. Conversely, LRCH1 expression inversely correlates with ulcerative colitis disease activity, and upregulation suppresses pathogenic CD4+ T cell migration 4. LRCH1 also negatively regulates post-traumatic spinal cord injury neuroinflammation by suppressing microglial pro-inflammatory cytokine production 5. Genetic variants in LRCH1 are associated with delayed encephalopathy after carbon monoxide poisoning 6 and shared cardiovascular-cerebrovascular disease susceptibility 7.