Dynamic PD-L1 Regulation Shapes Tumor Immune Escape and Response to Immunotherapy.

: A major challenge in cancer treatment is the ability of tumor cells to adapt to immunotherapy through immune escape, often mediated by the PD-1/PD-L1 pathway. To investigate this, we adapted an ordinary differential equation model of combination therapy, incorporating the dynamics of the immune checkpoint inhibitor Avelumab and the immunostimulant NHS-muIL12. : Using literature-derived parameter values, we refitted a single parameter across therapies, which showed that PD-L1 expression increased with immunotherapy, while Avelumab blocked its functional signaling, preventing PD-L1 from suppressing T-cell activity. Incorporating therapy-dependent, dynamically regulated PD-L1 expression enabled a biologically grounded mechanism to reproduce experimental observations, leading us to formulate PD-L1 tumor expression as a dynamic variable (ϵ) and providing a mechanistic basis for both therapeutic synergy and treatment failure. : We validated this mechanistic framework by showing that the distinct outcomes observed in two independent cancer datasets (EMT-6 and MC38) can be captured by the same model structure, differing only in the parameterization of tumor-specific parameters and PD-L1 regulatory dynamics. Our results indicate that tumor resistance is linked to dose-dependent upregulation of PD-L1 following NHS-muIL12 treatment, explaining treatment failure, while PD-1/PD-L1 blockade in combination therapy enables effective antitumor immune responses. : This work provides a validated mechanistic framework for adaptive resistance in combination immunotherapy. Quantified parameter differences between responder and non-responder phenotypes enable clearer biological interpretation and support the development of predictive tools for optimizing treatment strategies.