Single-cell transcriptome analysis indicates fatty acid metabolism-mediated metastasis and immunosuppression in male breast cancer

Male breast cancer (MBC) is a rare but aggressive malignancy with poor outcomes. The cellular states and immunological characteristics of MBC remain unclear. We performed a comparative analysis for transcriptomic data of 111,038 cells from six ER+ MBC and thirteen ER+ female breast cancer (FBC) samples. Single-cell T cell receptor sequencing (scTCR-seq) was also used to explore the difference of T cell clones between MBC and FBC. Results of single-cell RNA sequencing (scRNA-seq), bulk transcriptome, and immunohistochemistry consistently demonstrated that MBC had a significantly lower degree of T cell infiltration than FBC. Regulons controlled by AR and SREBF1, and metastasis-related programs were more active in cancer cells of MBC than FBC. Notably, the activated fatty acid metabolism involved by FASN was related to cancer cell metastasis and low immune infiltration of MBC. Different characteristics of T cell subpopulations between MBC and FBC were identified. T cells in MBC showed activation of p38 MAPK and lipid oxidation pathways, indicating the dysfunctional state. In contrast, T cells in FBC exhibited a higher expression level of cytotoxic markers such as GZMK and KLRB1, and activated pathways mediated by immune-modulatory cytokines. Moreover, we identified the inhibitory interactions between cancer cells and T cells in the MBC microenvironment, such as cell-cell communications mediated by TGF-β, TIGIT, and VSIR. Our study will provide important information for understanding the tumor immunology and metabolism of MBC, and promote the development of effective treatments for MBC.