Environmental enrichment suppresses colorectal cancer progression with comorbid depression by modulating the immunosuppressive tumor microenvironment.

Abstract

BACKGROUND: Depression compromises treatment efficacy across multiple cancer types, including colorectal cancer (CRC), largely through mechanisms that suppress antitumor immunity. Conversely, depression alleviation has been associated with improved cancer outcomes. Environmental enrichment (EE), a non-pharmacological lifestyle intervention, has been shown to ameliorate depressive-like behaviors; however, its ability to inhibit tumor growth in depression-comorbid CRC and the underlying mechanisms remain poorly defined. Here, we investigated the effects of EE on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and CRC progression. METHODS: A comorbid mouse model of depression and CRC was established by subcutaneously inoculating Balb/c mice with CT26 cells, followed by a CUMS paradigm. Following EE intervention, depressive-like phenotypes, inflammatory cytokine expression, and immune cell distribution/exhaustion profiles were evaluated using behavioral tests, enzyme-linked immunosorbent assay (ELISA), and multi-color flow cytometry, respectively. RESULTS: CUMS exposure markedly accelerated tumor growth, increased splenic index, and lowered survival rates. Immunological profiling revealed a concurrent expansion of regulatory T cells (Tregs) and TIM3exhausted CD8T cells, accompanied by reduced infiltration of functional CD8T cells. EE intervention improved measures of anhedonia and behavioral despair, delayed tumor progression, and mitigated CUMS-associated immunological alterations. Specifically, EE enhanced the presence of tumor-infiltrating CD8T cells, reduced the abundance of Tregs and exhausted CD8T cells, and restored physiological levels of pro-inflammatory cytokines. CONCLUSIONS: Our results demonstrate that EE effectively suppresses tumor growth in depression-comorbid CRC by remodeling the immunosuppressive tumor microenvironment. EE emerges as an attractive non-invasive intervention that may improve survival and quality of life in depressed CRC patients.