Tumor cells lacking MHC class I or expressing NK-activating ligands

Tumor cells lacking MHC class I or expressing NK-activating ligands represent a specific cellular phenotype that is highly susceptible to Natural Killer (NK) cell-mediated surveillance. According to the "missing self" hypothesis, the absence of Major Histocompatibility Complex (MHC) class I molecules—which normally provide inhibitory signals to NK cells—triggers an immune response (Ljunggren & Kärre, 1990). Additionally, these tumor cells often express stress-induced ligands such as MICA, MICB, or ULBPs that bind to activating receptors like NKG2D on NK cells (Vivier et al., 2011). This dual mechanism of reduced inhibition and increased activation makes these cells a primary focus for innate immunotherapy. Current therapeutic strategies include the use of NK cell engagers, checkpoint inhibitors like Monalizumab that block inhibitory receptors (e.g., NKG2A), and adoptive CAR-NK cell therapies (Shimasaki et al., 2020). These treatments aim to overcome tumor immune evasion and restore the body's ability to eliminate malignant cells that have bypassed T-cell recognition (Paul & Lal, 2017). This target phenotype is particularly relevant in the context of "cold" tumors that do not respond to traditional PD-1/PD-L1 T-cell checkpoint inhibitors.

Other names

MHC-I deficient tumor cellsNK-sensitive tumor cellsMissing-self phenotype tumorsHLA-deficient malignant cellsNK-activating ligand-positive tumor cells

Enhancement of Natural Killer (NK) cell-mediated cytotoxicity through the "missing self" recognition of MHC class I-deficient cells or the engagement of activating receptors by tumor-expressed ligands (Shimasaki et al., 2020).