A Mouse Model of Depression‐Tumor Multimorbidity Reveals the Mechanism of Tumor Growth Accelerated by Depression

ABSTRACT Depressive disorders are associated with accelerated tumor progression and poor clinical outcomes. Accumulating evidence indicates that psychiatric conditions and tumor development are tightly interconnected, yet the mechanisms by which depression remodels the tumor immune microenvironment remain poorly defined. To investigate how chronic stress influences tumor progression and host immunity, we established murine models of depression‐like behavior and depression‐tumor multimorbidity. Depression‐like phenotypes were validated through behavioral tests and hormone measurements, followed by comprehensive analyses of tumor growth and immune landscapes using transcriptomic sequencing, bioinformatic analyses, flow cytometry, and immunohistochemistry. Our results demonstrated that depressive states significantly promoted tumor growth. Transcriptomic profiling revealed widespread downregulation of multiple immune‐related pathways in depression‐associated tumors. Immunophenotyping further showed that depression markedly remodeled the tumor immune microenvironment, characterized by reduced intratumoral CD8 + T cell abundance, enhanced functional exhaustion, and increased PD‐1 expression, collectively contributing to impaired antitumor immunity. These findings indicated that depression accelerates tumor progression in parallel with the disruption of immune homeostasis and induction of CD8 + T cell dysfunction. This study underscores the importance of systemic crosstalk between behavioral states and tumor immunity in the context of depression‐tumor multimorbidity and provides a theoretical basis for integrating psychosocial interventions into cancer therapy. Furthermore, this work highlights the correlation between psychological state and tumor progression accompanied by systemic immune modulation, supporting the broader One Health perspective on the interconnection between physical and psychological multimorbidity.