Genetic alterations such as B2M mutations or deletions in antigen‐processing machinery (e.g., TAP1/2, ERAP1/2) are associated with clonal and irreversible MHC‐I loss, frequently observed in melanoma, colorectal, and lung cancers, and have been linked to primary resistance to PD‐1/PD‐L1 blockade. The gene discussed is B2M; the disease is lung carcinoma.