Research using the Collaborative Cross mouse model, designed for genetic variability, elucidates how inherited genetic differences impact tumor response to immune checkpoint inhibitors. Findings, published in Cell Reports, highlight gene-specific effects on therapy outcomes, addressing complexities akin to a 'three-body problem' involving tumor, immune system, and treatment interactions. The work advances understanding of patient stratification for immunotherapy and supports efforts to identify genomic markers predictive of treatment success, which remains challenging in genetically heterogeneous human populations.