How well a tumor responds to immunotherapy may depend in part on whether its chromosomes are intact or in a state of disarray, a new study reports. The finding could help doctors better pinpoint which cancer patients would benefit from immunotherapy. Cancer immunotherapy can produce durable clinical responses, but only in a subset of patients. Why certain patients benefit more than others is still unclear. Many tumors are characterized by "aneuploidy," meaning they display an abnormal number of chromosomes and chromosomal segments. A high degree of aneuploidy is a feature of high-grade tumors and is associated with poor prognosis. Here, Teresa Davoli and colleagues examined data from over 5,000 tumor samples representing 12 cancer types from The Cancer Genome Atlas (TCGA) project. The team found that high-aneuploidy tumors had increased expression of genes implicated in DNA replication, cell cycle, mitosis, and chromosome maintenance, yet decreased expression of genes characteristic of the infiltrating immune cells responsible for tumor destruction. In a retrospective analysis of clinical trial data, they found that melanoma patients with highly aneuploid tumors were less likely to benefit from immune checkpoint blockade therapy than patients whose tumors showed fewer chromosomal disruptions. These findings are highlighted in a Perspective by Maurizio Zanetti.