Methodological concerns regarding the role of GPD1L in Treg infiltration and lipid metabolism in clear cell renal cell carcinoma

Huang and Sun Journal of Translational Medicine https://doi.org/10.1186/s12967-025-07396-0 (2025) 23:1315 L E T T E R TO T H E E D I TO R Journal of Translational Medicine Open Access Methodological concerns regarding the role of GPD1L in Treg infiltration and lipid metabolism in clear cell renal cell carcinoma Weiping Huang1 and Aiwei Sun1* To the Editor: We read with great interest the article by Yang et al. [1] investigating the role of GPD1L as a biomarker linked to Treg infiltration and lipid metabolism in clear cell renal cell carcinoma (ccRCC). The study proposes a novel immune-metabolic axis and offers potentially valuable insights for prognosis and therapy. However, we have several methodological concerns that, in our view, potentially threaten the validity of the central conclusions regarding the mechanistic role of GPD1L. Our primary concern pertains to the evidence for a causal relationship between GPD1L downregulation and Treg cell infiltration. While the authors present compelling correlative data from bioinformatic analyses (e.g., Fig. 4A) and demonstrate that GPD1L overexpression reduces Treg density in mouse tumors (Fig. 8F), the study does not definitively establish causality. The observed reduction in Tregs could be a secondary consequence of inhibited tumor growth rather than a direct result of altered lipid metabolism modulating the immune microenvironment [2]. To substantiate the claim that GPD1L loss “facilitates adaptive survival via enhanced Treg infiltration,” more direct mechanistic studies are necessary. We suggest that utilizing Treg-specific coculture assays, conditional knockout models, or neutralization The online version of the original article can be found at https://doi.o rg/10.1186/s12967-025-06882-9. *Correspondence: Aiwei Sun 1 Department of Laboratory, Yangming Hospital Affiliated to Ningbo University(Yuyao City People’s Hospital), Yuyao, China antibodies would help dissect whether the effect is cell-autonomous or indirectly mediated by the tumor microenvironment. Furthermore, the translational validity of the cellular models used is a concern. The selection of cell lines based on the CCLE database (Fig. 2A) was not entirely consistent with internal validation, as the 786-O cell line showed discrepant GPD1L expression levels between the database and the authors’ own Western blot analysis (Fig. 2B-D). This inconsistency raises questions about the robustness of the model system [3]. Moreover, the functional conclusions are drawn primarily from two lowexpressing cell lines (769-P and Caki-1), which may not capture the full heterogeneity of ccRCC. Including gainof-function experiments in additional cell lines or using siRNA knockdown in high-expressing models would significantly strengthen the generalizability of the findings. Lastly, the claim that GPD1L is an independent prognostic biomarker is not fully supported, as the Cox regression analysis did not adjust for key clinical confounders. The univariate analysis (Supplementary Table 2) and the variation in GPD1L expression with T and M stage (Supplementary Fig. 1) strongly suggest that disease progression is a significant confounding variable [4]. For GPD1L to be convincingly presented as an independent prognostic factor, a multivariate Cox proportional hazards model including stage, grade, and age is essential. Without this, its purported prognostic value may be overstated. In conclusion, while the study by Yang et al. highlights a promising association, addressing these issues—particularly the need for causal evidence, robust model selection, and rigorous adjustment for prognostic confounders—is © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Huang and Sun Journal of Translational Medicine (2025) 23:1315 critical for validating the proposed mechanism and clinical relevance of GPD1L. Such validation is indispensable for guiding future research and potential therapeutic strategies not only in RCC but also in gastrointestinal malignancies where immune-metabolic crosstalk is of paramount importance. Acknowledgements Not applicable. Author contributions All authors contributed equally to manuscript drafting and critical revision. Funding Not applicable. Data availability Not applicable. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Page 2 of 2 Competing interests The authors declare no competing interests. Received: 11 September 2025 / Accepted: 13 September 2025 References 1. Yang M, Pang D, Gong C, et al. GPD1L as a potential biomarker associated with Treg cell infiltration and lipid metabolism in clear cell renal cell carcinoma. J Transl Med. 2025;23(1):872. https://doi.org/10.1186/s12967-025-0688 2-9. 2. Chang CH, Pearce EL. Emerging concepts of T cell metabolism as a target of immunotherapy. Nat Immunol. 2016;17(4):364–8. https://doi.org/10.1038/ni.3 415. 3. Ghandi M, Huang FW, Jane-Valbuena J, et al. Next-generation characterization of the cancer cell line encyclopedia. Nature. 2019;569(7757):503–8. https: //doi.org/10.1038/s41586-019-1186-3. 4. Hsieh JJ, Purdue MP, Signoretti S, et al. Renal cell carcinoma. Nat Rev Dis Primers. 2017;3:17009. https://doi.org/10.1038/nrdp.2017.9. 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