Tumor and stressed cells expressing activating NK ligands with reduced MHC-I

This target refers to a specific cellular state or phenotype rather than a single molecular entity. It is characterized by the downregulation of Major Histocompatibility Complex class I (MHC-I) molecules and the concomitant upregulation of activating ligands for Natural Killer (NK) cell receptors, such as MICA, MICB, and ULBPs (Shimasaki et al., 2020). This combination is a hallmark of many malignant and virally infected cells, which attempt to evade T-cell recognition by reducing MHC-I but consequently become targets for NK cells through the 'missing-self' and 'induced-self' recognition models (Lanier, 2005). In a therapeutic context, this phenotype is exploited by NK cell-based immunotherapies, including CAR-NK cells and checkpoint inhibitors that block inhibitory KIR or NKG2A receptors. Additionally, certain pharmacological agents like HDAC inhibitors can be used to sensitize tumors by upregulating the expression of activating ligands on the cell surface (Duan et al., 2021). Understanding this cellular profile is critical for developing strategies that enhance innate immune surveillance and overcome tumor-mediated immunosuppression.

Other names

Missing-self phenotypeInduced-self phenotypeNK-sensitive tumor cellsMHC-I deficient stressed cells

Natural Killer (NK) cells identify these cells through a dual-signal integration process: the 'missing-self' signal, where the absence or reduction of MHC-I molecules fails to engage inhibitory Killer-cell Immunoglobulin-like Receptors (KIRs), and the 'induced-self' signal, where stress-induced ligands (e.g., MICA/B) bind to activating receptors like NKG2D, triggering cytotoxic degranulation and cytokine release (Lanier, 2005; Ljunggren & Kärre, 1990).