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

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.

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.

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.

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.