To evaluate changes in tumor neoantigens during immune checkpoint blockade, Anagnostou, Smith, and colleagues performed whole-exome sequencing of pretreatment and post-progression tumor samples from patients with non–small cell lung cancer who developed resistance following treatment with anti–PD-1 or anti–PD-1/anti–CTLA-4. Loss of a subset of candidate mutation-associated neoantigens (MANA) was associated with the emergence of acquired resistance and occurred via elimination of neoantigen-harboring tumor subclones or chromosomal deletion of truncal mutations. Peptides encoded by the eliminated MANAs induced clonal expansion of neoantigen-specific T cells, indicative of functional immune responsiveness, and loss of these MANAs correlated with reduced T-cell receptor clonality. These findings suggest that immune editing of tumor neoantigens may promote acquired resistance to immune checkpoint inhibitors. For details, please see the article by Anagnostou, Smith, and colleagues on page 264.