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.
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.
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).
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.
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.
Ying Zhao, Xiao-Han Liu, Xin Bai et al.· Frontiers in Immunology· 0 citations
Background Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis and limited treatment options. Disulfidptosis, a novel cell death pathway driven by disulfide bond accumulation, has emerged as a potential mechanism in cancer biology; however, its role in ICC remains unclear. Methods We integrated single−cell RNA sequencing (GSE138709) with bulk transcriptomic datasets (TCGA−CHOL, GSE107943, GSE32225) to systematically characterize the ICC cellular landscape. Analyses included CNV inference, stemness scoring, disulfidptosis activity assessment, and cell−cell communication profiling. A diagnostic model was constructed using LASSO−logistic regression with 10−fold cross−validation and validated in independent cohorts. TME characterization, survival analysis, and drug−target screening were also performed. Experimental validation included HPA immunohistochemistry, qRT−PCR, and functional assays following TMED3 knockdown. Results Seven major cell types were identified, with malignant cholangiocytes exhibiting high aneuploidy (74%), elevated stemness, upregulated disulfidptosis activity, and extensive communication via SPP1−CD44 and IGFBP3−TMEM219 networks. A five−gene signature (TMED3, TMEM184B, MAPK13, MFSD10, GRB7) demonstrated robust diagnostic performance. Survival analysis showed borderline prognostic value for TMED3 (adjusted HR = 2.37, P = 0.073), while TMEM184B emerged as an independent prognostic factor (adjusted HR = 4.79, P = 0.028). PPI and co−expression analyses established links between signature genes and disulfidptosis regulators. Functional experiments confirmed that TMED3 knockdown suppressed ICC cell proliferation, migration, and enhanced sensitivity to glucose deprivation−induced disulfidptosis. Network−based drug screening identified eight high−priority candidates for therapeutic repurposing. Conclusion This study provides a comprehensive single−cell atlas of ICC, identifies TMED3 as a key regulator of a disulfidptosis−related diagnostic signature, and demonstrates its functional role in promoting ICC malignancy. The five−gene signature shows diagnostic and prognostic promise, and the drug screening offers preliminary leads for therapeutic repurposing, providing a foundation for precision diagnosis and targeted therapy in ICC.
Wan-Jia Qiao, Yixiang He, Jing Li et al.· Frontiers in Immunology· 0 citations
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