Using spatial statistics to infer game-theoretic interactions in an agent-based model of cancer cells.

Drug resistance in cancer is shaped not only by evolutionary processes but also by eco-evolutionary interactions between tumor subpopulations. These interactions can support the persistence of resistant cells even in the absence of treatment, undermining standard aggressive therapies and motivating drug holiday-based approaches that leverage ecological dynamics. A key challenge in implementing such strategies is efficiently identifying interaction between drug-sensitive and drug-resistant subpopulations. Evolutionary game theory provides a framework for characterizing these interactions. We investigate whether spatial patterns in single time-point images of cell populations can reveal the underlying game theoretic interactions between sensitive and resistant cells. To achieve this goal, we develop an agent-based model in which cell reproduction is governed by local game-theoretic interactions. We compute a suite of spatial statistics on single time-point images from the agent-based model under a range of games being played between cells. We quantify the informativeness of each spatial statistic and demonstrate that a simple machine learning model can classify the type of game being played. Our findings suggest that spatial structure contains sufficient information to infer ecological interactions. This work represents a step toward clinically viable tools for identifying cell-cell interactions in tumors, supporting the development of ecologically informed cancer therapies.