Oxeiptosis-associated transcriptional states, immune heterogeneity, and oxidative-stress susceptibility in triple-negative breast cancer
5 affiliations
- 1Department of Breast Cancer, Cancer Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University
- 2School of Medicine, Shantou University Medical College
- 3Department of Urology, Peking University First Hospital, Peking University
- 4Department of Family Medicine, Shengjing Hospital, China Medical University
- 5Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences
Abstract
Background: Triple-negative breast cancer (TNBC) exhibits substantial variation in treatment response. In the phase 2 NeoSAC trial, higher baseline oxeiptosis-associated transcriptional activity was associated with pathological complete response (pCR). However, the malignant-cell and immune features underlying this transcriptional state remain poorly defined, as do the molecular factors that influence cellular susceptibility to oxidative stress.
Methods: We integrated single-cell and bulk transcriptomic analyses to characterize oxeiptosis-associated tumor states and immune features in TNBC. CellChat was used to infer candidate intercellular communication patterns. An oxeiptosis-associated prognostic model was developed and evaluated in breast cancer cohorts. In MDA-MB-231 cells, ALG3 loss- and gain-of-function experiments were used to assess cellular responses to the KEAP1 activator VVD-130037. We also examined the effects of VVD-130037 alone and in combination with docetaxel on tumor-cell growth.
Results: TNBCs with higher oxeiptosis-associated transcriptional scores showed greater representation of memory T cells and selected dendritic and inflammatory myeloid populations. CellChat inferred differences in candidate MIF-related, SPP1-CD44, and MHC-associated communication patterns between the score-defined groups, suggesting the coexistence of immune engagement and regulatory features. A five-gene model comprising MAL2, TYMP, LIMCH1, ALG3, and PDLIM4 showed prognostic value across breast cancer cohorts, with moderate performance that varied between cohorts. VVD-130037 increased intracellular ROS and reduced AIFM1 Ser116 phosphorylation. N-acetyl-L-cysteine attenuated these responses and the accompanying growth inhibition, whereas z-VAD-fmk did not provide comparable protection against growth inhibition. ALG3 depletion reduced VVD-130037-induced ROS accumulation, attenuated AIFM1 Ser116 dephosphorylation, and decreased sensitivity to VVD-containing treatment. ALG3 overexpression promoted the VVD-associated decrease in AIFM1 Ser116 phosphorylation. VVD-130037 combined with docetaxel produced greater growth inhibition than either agent alone.
Conclusion: Oxeiptosis-associated transcriptional states were associated with distinct malignant-cell and immune features in TNBC. In MDA-MB-231 cells, ALG3 expression modified the cellular response to VVD-130037-induced oxidative stress. These findings warrant further investigation in independent clinical and experimental models.
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BibTeX
@article{zhuang2026oxeiptosisassociated,
title = {{Oxeiptosis-associated transcriptional states, immune heterogeneity, and oxidative-stress susceptibility in triple-negative breast cancer}},
author = {Ziyun Zhuang and Haiyu Zhang and Jiawei Lei and Changgui Zou and Yingcong Lin and Ciqiu Yang and Yitian Chen},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1938186},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1938186/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Oxeiptosis-associated transcriptional states, immune heterogeneity, and oxidative-stress susceptibility in triple-negative breast cancer
AU - Ziyun Zhuang
AU - Haiyu Zhang
AU - Jiawei Lei
AU - Changgui Zou
AU - Yingcong Lin
AU - Ciqiu Yang
AU - Yitian Chen
PY - 2026
DA - 2026/11/06
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1938186
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1938186/full
AB - Background: Triple-negative breast cancer (TNBC) exhibits substantial variation in treatment response. In the phase 2 NeoSAC trial, higher baseline oxeiptosis-associated transcriptional activity was associated with pathological complete response (pCR). However, the malignant-cell and immune features underlying this transcriptional state remain poorly defined, as do the molecular factors that influence cellular susceptibility to oxidative stress. Methods: We integrated single-cell and bulk transcriptomic analyses to characterize oxeiptosis-associated tumor states and immune features in TNBC. CellChat was used to infer candidate intercellular communication patterns. An oxeiptosis-associated prognostic model was developed and evaluated in breast cancer cohorts. In MDA-MB-231 cells, ALG3 loss- and gain-of-function experiments were used to assess cellular responses to the KEAP1 activator VVD-130037. We also examined the effects of VVD-130037 alone and in combination with docetaxel on tumor-cell growth. Results: TNBCs with higher oxeiptosis-associated transcriptional scores showed greater representation of memory T cells and selected dendritic and inflammatory myeloid populations. CellChat inferred differences in candidate MIF-related, SPP1-CD44, and MHC-associated communication patterns between the score-defined groups, suggesting the coexistence of immune engagement and regulatory features. A five-gene model comprising MAL2, TYMP, LIMCH1, ALG3, and PDLIM4 showed prognostic value across breast cancer cohorts, with moderate performance that varied between cohorts. VVD-130037 increased intracellular ROS and reduced AIFM1 Ser116 phosphorylation. N-acetyl-L-cysteine attenuated these responses and the accompanying growth inhibition, whereas z-VAD-fmk did not provide comparable protection against growth inhibition. ALG3 depletion reduced VVD-130037-induced ROS accumulation, attenuated AIFM1 Ser116 dephosphorylation, and decreased sensitivity to VVD-containing treatment. ALG3 overexpression promoted the VVD-associated decrease in AIFM1 Ser116 phosphorylation. VVD-130037 combined with docetaxel produced greater growth inhibition than either agent alone. Conclusion: Oxeiptosis-associated transcriptional states were associated with distinct malignant-cell and immune features in TNBC. In MDA-MB-231 cells, ALG3 expression modified the cellular response to VVD-130037-induced oxidative stress. These findings warrant further investigation in independent clinical and experimental models.
SN - 1664-3224
ER -