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
PURPOSE
To characterize irradiation-associated transcriptomic changes in murine triple-negative breast cancer cells and examine dose- and time-response patterns of selected radiation-responsive candidates.
MATERIALS AND METHODS
RNA sequencing (RNA-seq) was performed in 4T1 cells collected 24 h after 4 Gy irradiation, followed by Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and gene set enrichment analyses. Representative RNA-seq-derived genes were examined by reverse transcription quantitative PCR (RT-qPCR), and selected immune- and inflammation-related transcripts were further assessed across additional radiation doses and post-irradiation time points. Inducible nitric oxide synthase (NOS2) and triggering receptor expressed on myeloid cells 2 (TREM2) protein abundance was assessed by Western blotting, and nitrite accumulation in culture supernatants was measured using a Griess reagent-based assay as an indirect readout of nitric oxide production.
RESULTS
RNA sequencing identified 757 differentially expressed genes, including 285 upregulated and 472 downregulated genes. Irradiation was associated with enrichment of inflammatory, interferon-related, immune-system, and cell-adhesion transcriptional signatures, whereas downregulated genes were enriched in cell-cycle-, chromosome-cohesion-, DNA-damage-response-, DNA-repair-, and SUMOylation-related pathways. Selected immune- and inflammation-related transcripts showed distinct temporal patterns. Nos2 mRNA increased across the examined 0-6 Gy dose range and at later post-irradiation time points, whereas NOS2 protein showed different kinetics, with an early peak after 4 Gy irradiation and no clear further increase above 6 Gy. Nitrite accumulation increased after irradiation. Trem2 showed the largest fold increase among strongly upregulated transcripts identified by RNA-seq, but RT-qPCR detected a significant increase only at 24 h, and TREM2 protein abundance remained unchanged across the examined doses and time points.
CONCLUSIONS
Ionizing radiation was associated with broad bidirectional transcriptional remodeling in 4T1 cells, involving immune-, inflammatory-, and interferon-related signatures together with reduced representation of cell-cycle- and DNA-repair-related gene sets. The discordant mRNA and protein patterns of NOS2 and TREM2 indicate that transcript-level responses do not necessarily translate into corresponding protein-level changes. These findings define irradiation-associated molecular responses requiring further functional investigation.
Jing Li, Xin Bai, Wan-Jia Qiao et al.· International Journal of Rad...· 0 citations
Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with a poor prognosis; conventional treatments provide limited durable benefit, and resistance commonly develops. The introduction of immune checkpoint inhibitors (ICIs) has expanded treatment options for TNBC; however, ICI monotherapy has demonstrated limited efficacy, particularly in patients with advanced disease. Radiotherapy (RT) has long played a pivotal role in the treatment of early-stage and locally advanced breast cancer, as it not only exerts direct tumoricidal effects but also remodels the tumor immune microenvironment. In recent years, increasing attention has been directed toward the potential synergistic effects of ICIs and RT. This article reviews the immunological characteristics of TNBC, the current status of ICI-based therapy, and the underlying mechanisms of resistance. It also summarizes the biological rationale for combining RT with ICIs in the treatment of TNBC and, in light of recent advances in clinical research, explores the impact of different RT dose-fractionation regimens, treatment sequencing, and patient selection on therapeutic efficacy. Although current research remains in an early exploratory stage and several small studies have demonstrated the potential of this combination strategy, maximizing efficacy while controlling toxicity remains a key challenge for future clinical translation.
Lu Wang, Xin Bai, Fan Wang et al.· Frontiers in Immunology· 0 citations
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