Computational Framework for pH-Responsive Control of Tumor Microenvironment and Immune Dynamics

Abstract The acidic tumor microenvironment plays a central role in immune suppression and therapeutic resistance, yet acidity is often treated as a secondary consequence of tumor metabolism rather than an active dynamical variable. Here, we present a multiscale computational framework integrating tumor growth, immune dynamics, extracellular acidity, and engineered alkalinization control. The model couples ordinary differential equations for tumor and immune populations with reaction–diffusion dynamics governing spatial acidity and incorporates energetic constraints associated with therapeutic expression. Through steady-state, stability, bifurcation, and phase-space analyses, we identify distinct regimes of tumor persistence, bistability, and clearance governed by three dimensionless control parameters capturing dynamical, spatial, and energetic feasibility. The framework provides quantitative design principles for acidity-responsive therapeutic strategies and highlights physical constraints that shape effective tumor microenvironment modulation. These results establish a general modeling platform for studying pH-responsive tumor–immune interactions and guiding future experimental implementations. Keywords: synthetic biology, gene circuits, tumor microenvironment, computational modeling, cancer therapeutics, pH targeting, immunotherapy