Mathematical modeling and efficacy analysis of dual immune checkpoint blockade in breast cancer: Combination therapy with anti-PD-L1 and anti-CTLA-4

Combination immunotherapy targeting PD-L1 and CTLA-4 has emerged as a promising strategy in treating breast cancer. However, identifying an optimal dosing schedule remains challenging due to nonlinear dynamics within the tumor microenvironment (TME). While preclinical experiments demonstrate the synergy of dual blockade, the distinct functional and temporal roles of these checkpoints are rarely quantified within a unified framework: CTLA-4 regulates early T cell priming, whereas PD-L1 promotes effector T cell exhaustion. In this study, we develop a multiscale mathematical model calibrated against experimental data to characterize the dynamic interactions between these two pathways. The model integrates drug pharmacokinetics, cytokine signaling, and receptor-ligand binding kinetics. Model analyses indicate that coordinated high expression of PD-1 and PD-L1 is the major driver of immune escape, whereas CTLA-4 primarily constrains the magnitude of the initial T cell response. Furthermore, optimization of dosing schedules reveals that therapeutic efficacy critically depends on both administration sequence and dosing intervals. Specifically, sequential administration initiating with anti-CTLA-4 followed by anti-PD-L1 at shorter intervals markedly enhances antitumor immunity and achieves superior tumor regression compared with concurrent dosing. This study establishes a quantitative framework for the rational design of dual checkpoint blockade and provides predictive insights to guide clinical protocol optimization.