Modeling Bistable Dynamics Arising from Macrophage-Tumor Interactions in the Tumor Microenvironment

Abstract

Macrophages in the tumor microenvironment (TME), known as tumor-associated macrophages (TAMs), originate primarily from circulating monocytes that differentiate under the influence of tumor-derived signals. Within the TME, naive macrophages can adopt either a pro-inflammatory, anti-tumor (M1-like) or anti-inflammatory, pro-tumor (M2-like) phenotype. These pheno-typic shifts significantly affect tumor progression, making TAMs attractive targets for therapeutic intervention aimed at blocking recruitment, promoting anti-tumor polarization, or disrupting tumor-macrophage interactions. In this study, we develop a mathematical model capturing the temporal dynamics of tumor volume alongside populations of naive, M1-like, M2-like, and mixed (M1/M2) phenotype TAMs. The model incorporates the bidirectional influence between tumor development and macrophage polarization. We conduct the bifurcation as well as global sensitivity analyses to identify regions of bistability for tumor dynamics in the parameter space and the impact of sensitive parameters on TME. The model results are then linked to treatment strategies that may effectively induce transitions from high to low tumor burden. HighlightsO_LIWe propose a mathematical model to describe the temporal evolution of the tumor volume alongside different phenotypes of tumor-associated macrophages (TAMs). C_LIO_LIWe investigate the impact of TAMs on tumor growth and decline as well as the influence of the tumor on transition rates between different TAM phenotypes. C_LIO_LIBifurcation and global sensitivity analyses reveal the regions of bistability for tumor dynamics and the impact of sensitive model parameters on the tumor microenvironment. C_LIO_LIModel results are linked to treatment strategies that manipulate the bistable system to transition from high to low tumor volume. C_LI