Zhu M, Huang Y, Bender ME, et al. - Small cell lung cancer (SCLC) patients exhibit minimal responses to immune checkpoint blockade despite having a high tumor mutational burden, and this may be due to defects in immune surveillance, therefore researchers demonstrate that evading NK surveillance contributes to SCLC aggressiveness as well as metastasis, mainly via loss of NK cell recognition of these tumors by reduction of NK-activating ligands (NKG2DL). Very low level of NKG2DL mRNA was expressed by SCLC primary tumors and little to no surface NKG2DL was expressed by SCLC lines at the protein level. In preclinical models, tumor growth and metastasis were suppressed, in an NK cell-dependent manner, by restoring NKG2DL. Overall, findings demonstrate that a lack of stimulatory signals to engage and activate NK cells results from epigenetic silencing of NKG2DL, highlighting the underlying immune avoidance of SCLC and neuroblastoma.