Ying Zhao, Xiaohan Liu, Xin Bai, Jianming Tang
By explicitly distinguishing preclinical from clinical evidence and identifying knowledge gaps between mechanistic insights and clinical application, this review provides a framework for rational trial design and precision RT in BC.
BACKGROUND: Breast cancer (BC) is the most common malignant tumor among women worldwide. Radiotherapy (RT) is a primary treatment modality; however, local recurrence driven by radioresistance frequently undermines its efficacy.
MECHANISMS: Growing evidence indicates that breast cancer stem cells (BCSCs) and the tumor microenvironment (TME) cooperatively regulate multiple signaling pathways, thereby reducing RT efficacy. BCSCs exhibit intrinsic radioresistance through enhanced DNA repair capacity (Section 2.2.1), maintenance of redox homeostasis via the NRF2-KEAP1 and HIF-1α axes (Section 2.2.2), dysregulated cell cycle checkpoints (Section 2.2.3), and epithelial-mesenchymal transition (EMT) (Section 2.2.4). Concurrently, TME components-particularly cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs)-construct a protective niche that sustains BCSCs, promotes immune evasion, and triggers post-RT recurrence.
SUBTYPE-SPECIFIC HETEROGENEITY: The molecular subtyping of BC (Luminal A/B, HER2+, and triple-negative breast cancer (TNBC)) profoundly influences radiosensitivity and resistance mechanisms, necessitating subtype-specific therapeutic strategies (Section 2.1.2 and 3.1.1).
INTERVENTION STRATEGIES AND CHALLENGES: To overcome radioresistance, we discuss emerging combination approaches, including RT with immune checkpoint inhibitors (ICIs), BCSCs-directed agents, metabolic interventions, and nanodelivery systems. We critically appraise translational barriers, including the paucity of validated biomarkers, the plasticity of BCSCs, and the toxicity profiles of multimodal regimens.
CONCLUSION: By explicitly distinguishing preclinical from clinical evidence and identifying knowledge gaps between mechanistic insights and clinical application, this review provides a framework for rational trial design and precision RT in BC.