Mitoxyperilysis related signature predicts prognosis innate immune remodeling and myeloid enriched tumor microenvironment states in breast cancer

Background Breast cancer is highly heterogeneous in prognosis, immune composition, and therapeutic response. Mitoxyperilysis, a recently described mitochondria-dependent lytic cell death process linking innate immune activation, metabolic stress, and membrane rupture, may be relevant to tumor–immune remodeling, but its significance in breast cancer remains unclear. Methods We analyzed Mitoxyperilysis-related genes in TCGA-BRCA and constructed a prognostic signature using LASSO-Cox regression. Prognostic performance was evaluated by Kaplan–Meier analysis, time-dependent ROC curves, bootstrap validation, multivariable Cox regression, and decision curve analysis. WGCNA, Human Protein Atlas immunohistochemistry, immune profiling, cGAS-STING pathway analysis, programmed cell death scoring, single-cell RNA sequencing, spatial transcriptomics, and Western blot validation were integrated to characterize biological context. Results Thirteen of seventeen Mitoxyperilysis-related genes were dysregulated in breast cancer, and a 14-gene signature stratified patients into distinct survival groups. The signature showed moderate predictive performance and remained independently associated with overall survival after adjustment for age, AJCC stage, and PAM50 subtype. WGCNA and protein-level validation prioritized NLRP3, TLR4, NINJ1, and MYD88 as candidate hub genes. High-risk tumors exhibited reduced effector immune infiltration, increased suppressive immune features, cGAS-STING-linked innate immune remodeling, and coordinated suppression of multiple programmed cell death programs. Single-cell and spatial analyses further localized Mitoxyperilysis activity to myeloid-associated cellular states and spatially heterogeneous tumor regions. Conclusion This study identifies Mitoxyperilysis as a clinically relevant tumor–immune program in breast cancer and provides a framework for linking mitochondrial lytic cell death, immune suppression, and tumor microenvironment heterogeneity.