Transcriptomic Deconvolution Reveals Prognostic Immune Signatures and Immunotherapy-Responsive Subtypes in Male Breast Cancer

Background: Male breast cancer (MBC) is a rare malignancy with distinct biological and clinical features compared to its female counterpart. Emerging evidence suggests that a subset of MBCs may exhibit an immunogenic tumor microenvironment; however, the lack of sex-specific data on immune biomarkers has limited the inclusion of male patients in immunotherapy trials. Methods: We performed transcriptomic profiling of 123 MBCs, including 41 with germline pathogenic variants (PVs) in BRCA2 (n=26), BRCA1 (n=12), and PALB2 (n=3). Immune characterization included PD-1 and PD-L1 expression, immune scores, and immune cell infiltration using deconvolution tools. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was applied to predict potential response to immune checkpoint inhibitors. Results: A distinct subset of MBCs showed high PD-L1 expression and high immune scores. Immune deconvolution revealed that CD4+ memory resting T cells (24.5%), M2 macrophages (14.4%), and M0 macrophages (13.8%) were the most abundant infiltrating immune populations within the tumor microenvironment. Notably, 37.4% of tumors were predicted to respond to immunotherapy, primarily within the Luminal B subtype. These tumors demonstrated significantly higher PD-1/PD-L1 expression, higher immune scores, and enriched immune cell infiltration, compared to non-responders. Unsupervised clustering identified two transcriptionally distinct molecular subgroups. Cluster 1 was enriched for immune-related pathways and comprised the majority of predicted responders. Immune infiltration patterns varied significantly according to germline mutation status, intrinsic subtype, histological grade, androgen receptor expression, and Ki-67 proliferation index. Conclusions: This study identifies a transcriptionally defined, immunogenic subset of MBCs with potential sensitivity to immune checkpoint inhibitors. These findings highlight the need for sex-specific immune profiling and provide a rationale for incorporating immunotherapy into precision treatment strategies for men with breast cancer.