Dear editor
We read with great interest the article by Cheng et al. [1] recently published in the Journal of Translational Medicine. The authors present an elegant integration of single-cell and spatial transcriptomic profiling to delineate the evolving tumor microenvironment (TME) from ductal carcinoma in situ to invasive ductal carcinoma and lymph node metastasis. By resolving the intricate cellular dynamics across epithelial, stromal, and immune compartments, the study constructs a comprehensive spatiotemporal atlas that significantly deepens our understanding of tumor progression. Particularly noteworthy is the identification of the FAM111B-driven proliferative epithelial subpopulation and its dual vulnerability to cuproptosis and disulfidptosis, which highlights a promising metabolic–death coupling axis. We commend the authors for undertaking this ambitious and timely study, as their findings provide a valuable framework for understanding breast cancer evolution and may inform the development of novel therapeutic strategies targeting proliferative and immune-resistant phenotypes. While this work substantially advances the field, several aspects merit further elaboration and reflection. To strengthen clarity, we first emphasize the two principal limitations that directly affect interpretation, including the absence of spatial profiling in metastatic lymph nodes and the limited examination of immune escape mechanisms, followed by additional considerations that relate to future directions.
To begin with, although the authors successfully profiled over 140,000 cells and defined multiple epithelial, stromal, and immune subclusters, the integration of spatial transcriptomics excluded lymph node samples, thereby limiting the resolution of metastatic niche organization. The reported disappearance of the CD4⁺ T-cell and macrophage-enriched ecological subtype (Ecotype 1) in IDC suggests a progressive erosion of anti-tumor immunity. Without spatial validation in LM tissues, however, the precise trajectory of this ecological collapse remains inferential. Inclusion of spatial datasets from metastatic lesions could provide a more complete picture of how cellular adjacency and immune–stromal interactions evolve to favor metastatic colonization. Such immune-ecological remodeling has been previously recognized as a determinant of therapeutic responsiveness within the tumor immune microenvironment [2].
Another important consideration concerns the epithelial transcriptional programs identified across disease stages. While FAM111B was functionally validated as a key proliferative driver within the C5 subtype, FAM111B is also known to participate in DNA replication, cell cycle progression, and replication stress responses, and these biological activities provide additional support for its potential influence on both proliferative and immune regulatory pathways. Recent studies further show that FAM111B promotes mitochondrial homeostasis and metabolic adaptation through MFN2 degradation, and also enhances proliferation via MYC, thereby reinforcing its relevance to malignant progression in epithelial tumors [3, 4]. The transcriptomic analysis also revealed marked downregulation of immune interactive and stress response programs, particularly those related to MHC class I and MHC class II antigen presentation, which were not further examined. Because proliferative activation and immune evasion often appear together as hallmarks of malignant adaptation, evaluating how FAM111B may affect antigen processing, interferon related signaling, or DNA repair activity would substantially enhance the mechanistic depth of the study.
A further point worthy of discussion is the authors’ interpretation of dual sensitivity to cuproptosis and disulfidptosis within proliferative epithelial cells. This hypothesis is compelling, yet these two forms of cell death are tightly governed by mitochondrial metabolism and redox balance, which fluctuate under different microenvironmental conditions. Quantitative assessment of intracellular copper content, oxygen consumption rate, and cystine uptake—combined with perturbation of FDX1 and SLC7A11—could help determine whether these susceptibilities reflect intrinsic metabolic wiring or context-induced vulnerability shaped by the TME. Recent studies have elegantly characterized the molecular basis of both cuproptosis and disulfidptosis [5], supporting the plausibility of such metabolic–death crosstalk.
Finally, and perhaps most critically, the study lacks in vivo experimental confirmation. While the in vitro assays convincingly demonstrate that FAM111B silencing impairs proliferation and invasion, validation in animal models or patient-derived xenografts would be essential to verify whether FAM111B indeed confers proliferative and metastatic advantage in physiological settings. Among available approaches, orthotopic transplantation models and patient derived xenografts are particularly suitable because they preserve relevant tissue architecture and microenvironmental features that are required to evaluate the biological consequences of FAM111B activity in living systems. Linking the multi-omic insights with in vivo tumor dynamics would bridge the gap between molecular discovery and clinical translation.
In summary, Cheng et al. have delivered an insightful and technically robust study that illuminates the spatial and molecular choreography of breast ductal carcinoma progression. By incorporating spatial analysis of metastatic sites, expanding mechanistic interrogation, and establishing in vivo evidence, the clinical relevance of FAM111B-driven metabolic reprogramming could be further strengthened. We hope that these reflections may assist in refining future research directions and, ultimately, contribute to translating these discoveries into tangible therapeutic advances for patients with breast cancer.
Acknowledgements
Not applicable.
Author contributions
Boyang Li: Literature review, Conceptualization, Writing – original draft. Lucy Yue Lau: Writing – review and editing. Yi Chen: Conceptualization, Supervision, Writing – review and editing.
Funding
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Data availability
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Declarations
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Competing interests
The authors declare no competing interests.
Footnotes
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References
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Data Availability Statement
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