Dynamic cancer dormancy and awakening emerge from tumor microenvironment feedback in a minimal theoretical model

Cancer cell dormancy is characterized by late relapse and therapy resistance, yet the mechanisms that awaken dormant cells remain poorly understood. The tumor microenvironment has emerged as a key driver of these state transitions. Here we present a theoretical framework based on evolutionary game theory in which interactions between cancer and host cells are coupled explicitly to a changing tumor microenvironment. Cancer cells produce a conditioning factor that is cleared by the microenvironment and tolerated only up to a threshold. Through this conditioning factor, the microenvironment feeds back on cancer-host interactions and reshapes their competitive balance. Unlike a model with fixed interactions, this feedback allows dormancy and awakening to emerge as dynamic outcomes of microenvironmental change. We show that this minimal coupling is sufficient to generate distinct long-term regimes. Across these regimes, feedback generates thresholds and history dependence, so that the same cancer population can follow different fates depending on whether the microenvironment is already primed. Our framework reduces these dynamics to experimentally and biologically interpretable parameters linked to conditioning factor production, clearance, tolerance, and microenvironment-dependent changes in cancer-host competition. More broadly, it provides a quantitative basis for testing how collective microenvironmental feedback shapes cancer dormancy and awakening, and for designing experiments to uncover the mechanisms that awaken dormant cancer cells.