Domain shift in histopathology, often caused by differences in acquisition processes or data sources, poses a major challenge to the generalization ability of deep learning models. Existing methods primarily rely on modeling statistical correlations by aligning feature distributions or introducing statistical variation, yet they often overlook causal relationships. In this work, we propose a novel causal-inference-based framework that leverages semantic features while mitigating the impact of confounders. Our method implements the front-door principle by designing transformation strategies that explicitly incorporate mediators and observed tissue slides. We validate our method on the CAMELYON17 dataset and a private histopathology dataset, demonstrating consistent performance gains across unseen domains. As a result, our approach achieved up to a 7% improvement in both the CAMELYON17 dataset and the private histopathology dataset, outperforming existing baselines. These results highlight the potential of causal inference as a powerful tool for addressing domain shift in histopathology image analysis.