Mutant p53 Gain-of-Function and Immune Suppression: Mathematical Modeling of STING–TBK1–IRF3 Axis Restoration for Enhanced Cancer Therapy

Abstract

Cancer progression is frequently driven by mutations in the tumor suppressor gene TP53. These mutations cause the protein to lose its normal growth-inhibitory functions and acquire new properties that promote tumor development and immune evasion. Recent experimental studies show that mutant p53 (mutp53) suppresses the immune system by binding to TANK-binding kinase 1 (TBK1). This interaction blocks the formation of the Stimulator of Interferon Genes (STING)-TBK1-interferon regulatory factor 3 (IRF3) signaling complex, which is essential for inducing Type I interferon (IFN-I) production. Consequently, the anti-tumor immune response is weakened. Despite increasing experimental evidence for the mutp53-TBK1 interaction, the quantitative impact of this axis on tumor-immune dynamics remains poorly understood. In particular, it is unclear how modulation of mutp53 or restoration of TBK1 activity influences long-term tumor control at the systems level. To investigate the potential benefits of mutp53-TBK1-based therapeutic interventions, we developed a mathematical model based on a system of ordinary differential equations (ODEs). This proposed model captures the dynamic interplay between tumor growth, immune effector cells, IFN-I, and the intracellular STING-TBK1-IRF3 signaling axis regulated by mutp53. Parameter uncertainty was explored using Latin Hypercube Sampling (LHS), and the resulting model outputs were analyzed using Partial Rank Correlation Coefficients (PRCC) to evaluate parameter significance and model robustness. Numerical simulations yield key predictive insights into tumor-immune dynamics. First, in the absence of treatment, the model indicates that mutp53-mediated suppression of innate signaling drives immune escape and sustained tumor progression. Second, under simulated therapeutic conditions, the results suggest a profound divergence in treatment robustness: shRNA-mediated knockdown of mutp53 is predicted to yield highly consistent tumor suppression regardless of the baseline immune state. Conversely, the efficacy of ectopic TBK1 overexpression relies heavily on existing immune recruitment, with its impact diminishing significantly in immunologically 'cold' environments. Finally, the model predicts that combining both interventions produces a strong synergistic antitumor effect, achieving the greatest reduction in tumor burden. These theoretical results, which quantitatively align with recent experimental observations, underscore the critical need to simultaneously target upstream mutp53 oncogenic signaling and augment downstream TBK1 induction to successfully re-establish effective immune surveillance.