BRCA1 at the Crossroads of Genome Stability, Mitochondrial Homeostasis, and Tumor Immunity

Abstract BRCA1 has long been recognized as a guardian of genome integrity through its essential role in homologous recombination (HR)-mediated DNA repair. While HR deficiency underlies the clinical efficacy of Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), therapeutic responses remain incomplete, highlighting the need to identify vulnerabilities beyond defective DNA repair. Recent evidence has expanded the biological landscape of BRCA1, revealing critical roles in mitochondrial (mt) quality control, metabolic homeostasis, redox regulation, and innate immune signaling. Together, these functions support an integrated genome-mitochondria-immune axis through which BRCA1 coordinates cellular adaptation to stress. Disruption of this network amplifies genomic instability, promotes metabolic rewiring and inflammatory signaling, and generates vulnerabilities extending beyond HR deficiency. Mitochondrial dysfunction resulting from BRCA1 loss reinforces tumor progression through mitochondrial DNA (mtDNA) instability, oxidative stress, and tumor microenvironment remodeling while creating opportunities for therapeutic intervention. Viewing BRCA1 deficiency through this integrated framework broadens the concept of synthetic lethality and provides a rationale for combination strategies integrating PARP inhibition with mitochondrial-targeted agents, metabolic therapies, epigenetic modulators, and immune-based approaches. This perspective positions BRCA1 as a central regulator of nuclear-mitochondrial crosstalk and highlights emerging opportunities to overcome therapeutic resistance and advance precision oncology.