A case report describes durable responses to pembrolizumab in two patients with microsatellite-unstable metastatic colorectal cancer and markedly reduced HLA class I (HLA-I) expression. The observations suggest a scenario where T cells cannot recognize tumor antigens effectively, raising the possibility of NK-cell–mediated antitumor activity. While limited to individual cases, the biology aligns with growing mechanistic work on immune escape via antigen presentation loss and the compensatory roles of innate immune effectors. For trial design, the key translational question is whether HLA-I–low biomarkers can help identify patients likely to benefit from checkpoint blockade strategies that recruit or harness NK function.