Computational Modeling of an Acidity-Responsive Regulatory Gene Circuit in Tumor–Immune Microenvironment Dynamics

Background: Tumor microenvironments (TMEs) frequently exhibit extracellular acidity (pH ~6.5), a biophysical feature known to play a critical role in cellular behavior, tumor progression, immune suppression, and altered therapeutic response. While synthetic regulatory circuits capable of sensing acidity have been proposed, quantitative frameworks describing how microenvironmental pH dynamics interact with tumor–immune systems remain limited. Methods: We developed a computational modeling framework describing acidity-mediated regulatory dynamics in coupled tumor–immune systems. The model integrates interacting processes including tumor population dynamics, effector T-cell activity under acid-dependent suppression, regulatory vector dynamics, pH-responsive promoter activation, buffering or alkalinization mechanisms, cytokine-mediated feedback, and proton concentration kinetics calibrated to physiological pH ranges (6.0–7.4). Alternative acidity-modulating strategies, including substrate-dependent and substrate-independent buffering mechanisms, were examined through parameter sweeps, sensitivity analysis, and spatial reaction–diffusion extensions. System behavior was analyzed using stability and regime characterization methods. Results: The model exhibits distinct dynamical regimes in which acidity modulation reshapes tumor–immune interactions. Simulation of the acidity-responsive regulatory module demonstrated that promoter-driven therapeutic activation reduces tumor burden through two mechanistically distinct pathways. The alkalinization strategy elevated steady-state pH (ΔpH ≈ 0.2–0.6), partially restoring immune activity and reducing tumor persistence via microenvironmental feedback. In contrast, immune reactivation enhanced cytotoxic pressure directly, producing more rapid tumor suppression without substantially normalizing extracellular pH. In both architectures, therapeutic output increased under acidic conditions and diminished as pH approached physiologic levels, demonstrating dynamically coupled and self-limiting behavior. Sensitivity and scaling analyses further revealed hierarchical parameter control and architectural differences between substrate-dependent and substrate-independent buffering mechanisms. Conclusions: This study provides a quantitative theoretical framework for understanding how microenvironmental acidity functions as a regulatory variable in tumor–immune dynamics. The results highlight generalizable principles governing acidity-mediated feedback, system stability, and scaling behavior, offering mechanistic insights relevant to microenvironment-responsive regulatory systems. These findings emphasize the importance of biophysical microenvironmental factors in shaping cellular system dynamics and provide a basis for future experimental investigation of acidity-responsive biological regulation.