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

Abstract 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 adapt an evolutionary game theory framework with environmental feedback to the cancer dormancy setting, coupling cancer–host interactions to a changing tumor microenvironment. Cancer cells are assumed to produce a local conditioning factor that is cleared by the microenvironment and alters cancer–host competition once it approaches a characteristic concentration or activity scale. 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, the environmental load determines whether conditioning can become strong enough to shift the outcome toward cancer dominance. Furthermore, in the colonization/priming endpoint, prior niche conditioning can also create history dependence, so that the same cancer population can follow different fates depending on whether the microenvironment is already primed. Repeated small waves of arriving cells can also cross this boundary cumulatively, and closeness to either threshold generates large variation in the time to outgrowth. Our model reduces these dynamics to biologically interpretable parameters linked to conditioning factor production, clearance and tolerance, together with 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 once a specific conditioning process is defined, in order to uncover the mechanisms that awaken dormant cancer cells.