Inverse game theory characterizes frequency-dependent selection driven by karyotypic diversity in triple-negative breast cancer.

Chromosomal instability, characterized by pervasive copy number alterations (CNAs), significantly contributes to cancer progression and therapeutic resistance. CNAs drive intratumoral genetic heterogeneity, creating distinct subpopulations whose interactions shape tumor evolution through frequency-dependent selection. Here, we introduce ECO-K (Ecological-Karyotypes), an inverse game theory framework that quantifies frequency-dependent interaction coefficients among karyotypically defined subpopulations under the assumption that their fitness is frequency-dependent. Applying this approach to serially-passaged, triple-negative breast cancer cell lines and patient-derived xenografts (PDXs), we estimated interaction matrices consistent with the observed time-series dynamics. In one PDX lineage, the inferred matrices consistently assigned large interaction coefficients to a subpopulation characterized by chromosome 1 loss and chromosome 14p gain, suggesting it may act as an ecological hub within the frequency-dependent model. Our framework provides testable predictions of intratumoral ecological dynamics, highlighting opportunities to strategically target key subpopulations to disrupt tumor evolution.