A multiscale model reveals how ERK/p38-regulated dormancy shapes tumor-immune dynamics and immunoediting outcomes.

Introduction: Immune responses in cancer arise from dynamic interactions across biological scales, linking intracellular signaling, cellular phenotypic plasticity, and tumor-immune dynamics. Cancer cell dormancy is increasingly recognized as a continuous and heterogeneous phenotype driven in part by ERK and p38 signaling, yet most existing models represent it as a binary state, limiting their ability to capture its regulatory role in immune-mediated tumor control. Methods: Here, we introduce a new ERK-p38-structured model of cancer-immune cells in which tumor cells are continuously stratified along an ERK/p38 phenotypic axis. This framework provides a systems description that preserves both computational efficiency and theoretical tractability. It links intracellular signaling to cellular behavior and population-level dynamics by describing phenotype-dependent proliferation, immune susceptibility, and stress responses driven by growth factors, immune pressure, stress, and therapy. Results: Using this model, we show that the distribution of tumor phenotypes governs the emergent regimes of tumor-immune dynamics, including elimination, equilibrium, and escape. The model further predicts that increased p38 activation in response to immune pressure promotes immune evasion, whereas stress-induced p38 signaling drives global tumor dormancy. Conversely, p38 inhibition shifts the phenotype distribution toward more proliferative states, which enhances tumor sensitivity to immune-mediated killing and therapeutic interventions. To provide mechanistic insight, we derive a reduced model and identify critical thresholds in the mean ERK/p38 phenotype that determine tumor fate. Discussion: Together, these results suggest that phenotypic plasticity is a key regulator of immunoediting and provide a quantitative multiscale framework linking intracellular signaling to immune-driven tumor dynamics, with implications for understanding immune evasion and improving therapeutic responses.