Using the genetically diverse Collaborative Cross mouse model, researchers demonstrated that genetic variability influences tumor response to immune checkpoint inhibitors. This work, published in Cell Reports, highlights gene-specific effects on immunotherapy outcomes, elucidating the complexity akin to the 'three-body problem' where immune, tumor, and therapy interactions are difficult to predict. Findings offer insights into which patients might benefit most from checkpoint therapy, addressing challenges posed by human genetic heterogeneity and informing personalized cancer treatment strategies.