Pan-Cancer Analysis of a Depression-Related Gene Signature Identifies an Immunosuppressive Tumor Microenvironment and Links to Immunotherapy Response in Breast Cancer

Background: Depression has been increasingly associated with cancer progression and patient outcomes, yet its molecular and immunological correlates within tumors remain incompletely understood. This study aimed to investigate depression-associated gene signature across cancers and evaluate their relationship with tumor biology, immune microenvironment, and clinical outcomes, with a focus on breast cancer. Methods: A depression-related gene signature comprising 382 genes was obtained from the Molecular Signatures Database and used to compute a DScore via single-sample gene set enrichment analysis (ssGSEA) across over 10,000 tumor samples from 33 cancer types in The Cancer Genome Atlas (TCGA). Tumor microenvironment features were assessed using ESTIMATE and CIBERSORT, and cell-type-specific patterns were evaluated using single-cell RNA sequencing. CACNA1H was validated using qPCR and IHC in breast cancer samples. Results: DScore exhibited tissue-specific patterns across cancers and was elevated in several tumor types, including gastrointestinal, brain, renal, and endocrine malignancies. Higher DScore was associated with older age, advanced stage, and poorer survival across multiple malignancies, including breast, ovarian, uterine, and lung cancers, whereas inverse associations with survival were observed in selected brain, kidney, and endocrine cancers. Higher DScore was further associated with genomic instability, an immunosuppressive tumor microenvironment (TME), and poorer survival across multiple cancers, particularly in breast and ovarian cancers. In breast cancer, this phenotype was characterized by monocytic-lineage enrichment, increased M2 macrophages, and reduced CD8⁺ T-cell infiltration. Consistent with these findings, higher DScore was associated with reduced benefit from immune checkpoint therapy in breast and bladder cancers, with non-responders exhibiting higher DScore predominantly enriched in monocytic-lineage cells. CACNA1H was identified as a depression-related gene correlated with poor prognosis in breast cancer and was validated in independent cohorts. Conclusion: Depression-associated gene expression patterns are linked to tumor biology and immune features across cancers, with particularly strong relevance in breast cancer. These findings highlight the need for further research into how psychological, molecular, and immune factors interact in cancer progression and treatment response.