A new study in Genome Medicine tied a specific genomic instability profile to immunotherapy sensitivity in microsatellite-stable colorectal cancer. Researchers reported that low chromosomal instability identifies a subset responsive to anti-PD-1 therapy and that the population could be further sensitized by bortezomib. The work frames chromosomal instability as a practical stratification axis for colorectal tumors that otherwise show limited benefit from checkpoint blockade. If reproduced prospectively, the biomarker could support more targeted combination designs and reduce trial-and-error selection in CRC treatment.