Concerns regarding lipid metabolism, immune regulation, and methodology in a study on esophageal cancer lymph node metastasis

Abstract

This letter comments on a study on lipid metabolism, immunity, and lymph node metastasis in esophageal cancer, a clinically relevant topic given lipid-immune crosstalk in tumor progression, to be published by the World Journal of Gastrointestinal Surgery. Key concerns include the following: Lack of detailed lipid parameter data [especially low-density lipoprotein (LDL) distribution] to contextualize LDL-metastasis associations, unclear criteria for selecting LDL receptors/ LDL receptor-related protein family genes and unexplained exclusion of broader lipid metabolism genes, and a disconnect between the proposed LDL-B lymphocyte regulatory hypothesis and literature emphasizing cholesterol’s impact on T cells. We therefore suggest that future research should supplement lipid data, clarify gene selection rationale, and provide direct evidence for LDL-B lymphocyte interplay, in order to enhance reliability in understanding esophageal cancer lipid-immune regulation.

Core Tip: This letter raises concerns about a study investigating lipid metabolism and lymph node metastasis in esophageal cancer, focusing on three key issues: Insufficient data on lipid parameters [especially low-density lipoprotein (LDL) distribution] in the patient cohort, unclear rationale for selecting LDL-related genes and excluding other lipid metabolism pathways in gene screening, and a lack of direct evidence supporting the proposed LDL-B lymphocyte regulatory axis. It emphasizes the complexity of lipid-immune crosstalk in tumors and suggests future studies address these points to strengthen conclusions on lipid-immune regulation in esophageal cancer.

TO THE EDITOR

We are writing this letter to comment on the study[1] exploring the relationship between lipid metabolism, immune regulation, and lymph node metastasis in esophageal cancer, to be published in the World Journal of Gastrointestinal Surgery.

This topic holds significant clinical and scientific relevance, as lipid metabolism and immune crosstalk have emerged as critical regulators of tumor progression and metastasis. However, upon careful review, we raise several concerns related to methodology, data interpretation, and supporting evidence that require further clarification to strengthen the study’s conclusions as follows.

Inadequate reporting of key lipid parameter data in the patient cohort

While the inclusion criteria explicitly list key lipid parameters [triglycerides, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein, apolipoprotein-A1, apolipoprotein-B, lipoprotein (a) as variables to be examined, the study lacks a detailed description and analysis of these metrics in the enrolled patient cohort. Specifically, there is a notable absence of data on the LDL levels among the study population, which is central to the core hypothesis. This limits the ability to contextualize the observed associations between LDL and lymph node metastasis.

Unclear rationale for gene selection and exclusion of broader lipid metabolism pathways

With regard to the methodology for gene screening, although the study focuses on LDL receptors and LDL receptor-related protein (LRP) family members (e.g., LRP6) identified via tumor gene databases, the process by which these specific receptors were selected is not adequately described. The criteria for prioritizing LDL receptors and LRP family members over other potential candidates remain unclear, making it difficult to assess the rigor of the screening strategy. Furthermore, the rationale for focusing exclusively on LDL in weighted gene co-expression network analysis is not explicitly justified. Given the established role of cholesterol and other lipid metabolites in tumor biology, the exclusion of key genes involved in broader lipid metabolism pathways requires explanation. For example, recent research by Deng et al[2] demonstrated that in metastatic esophageal squamous cell carcinoma, tumor cells upregulate the expression of ANO1. ANO1 alters cholesterol metabolism and stimulates fibroblast activity through both cell-intrinsic and cell-extrinsic mechanisms. Its key role lies in inhibiting the liver X receptor pathway, resulting in increased intracellular cholesterol accumulation. This process is mediated by the interaction between ANO1 and the transcription factor JUN, which represses the expression of CYP27A1 and induces the secretion of interleukin (IL)-1β.

Disconnect between the proposed LDL-B lymphocyte hypothesis and supporting evidence

In the discussion, the authors suggest a regulatory role of LDL in B lymphocytes, stating: “Although there is no supporting evidence to confirm the regulatory role of LDL in B lymphocytes, the secretion of IL-10 in B lymphocytes depends on cholesterol metabolism and high cholesterol levels lead to the depletion of CD8⁺T cells, supporting our hypothesis”. However, the cited literature primarily supports the impact of cholesterol metabolism on T cells, rather than direct interactions between LDL and B lymphocytes. This creates a disconnect between the hypothesis and the supporting evidence, weakening the argument for a specific LDL-B lymphocyte axis.

Complexity of lipid-immune crosstalk in tumors: Context from recent advances

Recent advances in lipid metabolism research highlight its critical role in tumor cell metabolic reprogramming (Figure 1)[3]. Cholesterol and lipid biosynthesis are key drivers of tumor microenvironment remodeling. As demonstrated in the study by Ciavattone et al[4], fatty acids (FA) and cholesterol, as central lipid metabolites, enter T cells via transporters such as cluster of differentiation 36 or FA transport proteins, inducing effector T cell exhaustion, activating peroxisome proliferator-activated receptor beta and FA oxidation in regulatory T cells. Furthermore, studies by Li et al[5] and Dai et al[6] have shown that cholesterol may impair antigen presentation, suppressing Toll-like receptor signaling, inhibiting dendritic cell proliferation and modulating macrophage polarization. These processes underscore the complexity of lipid–immune crosstalk in tumors (Figure 2)[3].

Figure 1.

Metabolic reprogramming in the tumor microenvironment[3]. In the tumor microenvironment, disorganized blood vessels deliver glucose and oxygen, mostly taken up by tumor cells, leading to hypoxia and glucose deprivation. Tumor cells show activated glycolysis, producing more lactic acid but insufficient energy. Lipoprotein lipase from tumor and stromal cells activates adipocytes, inducing lipolysis of triglycerides and fatty acid (FA) secretion; FAs enter cells via CD36 or FA transport proteins. Tumor cells also generate FAs de novo using acetyl-CoA from glucose catabolism, involving acetyl-coA carboxylase and FA synthase. These FAs participate in FA oxidation or other pathways, producing immunosuppressive factors or forming lipid droplets. Additionally, lipoproteins in the microenvironment are transported via lipoprotein receptors and catabolized to cholesterol intracellularly; tumor cells also synthesize cholesterol via the mevalonate pathway. Dysregulated lipid metabolism in tumor cells promotes an acidic, hypoxic, glucose-deprived, and lipid-rich immunosuppressive microenvironment. Citation: Yu W, Lei Q, Yang L, Qin G, Liu S, Wang D, Ping Y, Zhang Y. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment. J Hematol Oncol 2021; 14: 187. Copyright ©The Author(s) 2021. Published by Biomed Central (Supplementary material). LPL: Lipoprotein lipase; FA: Fatty acid; FATP: Fatty acid transport protein; FAO: Fatty acid oxidation; LD: Lipid droplet; LR: Lipoprotein receptor.

Figure 2.

Lipid metabolism in pro-tumor immune responses[3]. A: Fatty acids (FAs) taken up via CD36 or FA transport proteins mediate immunosuppression by inducing effector T cell (Teff) exhaustion or stimulating PPAR-β and FA oxidation (FAO) in regulatory T cells (Tregs). FoxP3 regulates FA metabolism in Tregs to exert immunosuppressive effects. Cholesterol induces programmed cell death protein 1 (PD-1) and 2B-4 expression, promoting Teff exhaustion to drive tumor growth. Leptin in the tumor microenvironment (TME) suppresses Teff via the PD-1-STAT3-CPT1B pathway, enhancing FAO and reducing cytotoxicity; B: In macrophages, FAs taken up via transporters or synthesized de novo stimulate CPT1B and FAO, enhancing secretion of immunosuppressive cytokines [e.g., arginase 1 (ARG-1), interleukin (IL)-10] or suppressing pro-inflammatory cytokines (e.g., tumor necrosis factor-α, IL-6, IL-1β). Macrophage colony-stimulating factor (M-CSF) from the TME upregulates FA synthase (FASN) expression. Macrophages with high ABCG1 expression transport cholesterol out, promoting IL-4 secretion and tumor progression; C: MSR1 and TGFBR1 facilitate FA transport and lipid droplet (LD) formation in dendritic cells (DCs), influencing antigen processing, Toll-like receptor stimulation, and DC proliferation; D: CD36 on myeloid-derived suppressor cells (MDSCs) mediates uptake of polyunsaturated FAs, activating STAT3/5 and inducing reactive oxygen species production. M-CSF promotes FASN and FA production in MDSCs, enhancing secretion of immunosuppressive cytokines (e.g., IL-10, ARG-1, inducible nitric oxide synthase); E: FAs suppress natural killer cell cytotoxicity via the mTOR (mechanistic target of rapamycin)-PPAR signaling pathway; F: Neutrophils accumulate LDs due to elevated exogenous FA uptake and downregulated adipose triglyceride lipase by PGE2. LDs in neutrophils are transported to tumor cells to promote proliferation. Oxysterol enhances neutrophil migration by binding to CXCR2. Citation: Yu W, Lei Q, Yang L, Qin G, Liu S, Wang D, Ping Y, Zhang Y. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment. J Hematol Oncol 2021; 14: 187. Copyright ©The Author(s) 2021. Published by Biomed Central (Supplementary material). M-CSF: Macrophage colony-stimulating factor; NK: Natural killer; PD-1: Programmed cell death protein 1; DC: Dendritic cell; MDSC: Myeloid-derived suppressor cell; ROS: Reactive oxygen species.

CONCLUSION

The current literature review on B cell-lipid metabolism interactions appears insufficient. To reinforce the conclusions, we suggest that future studies should present detailed data on blood lipid levels (including LDL) in the 294 esophageal cancer patients and their correlation with pathological outcomes; clarify the rationale for selecting LDL-related genes over other lipid metabolism pathways; and provide more direct evidence for the proposed interplay between LDL and B lymphocytes. Addressing these points will enhance the robustness of the findings and their contribution to understanding lipid–immune regulation in esophageal cancer (Figure 3).

Figure 3.

The original study exhibits critical limitations across three core dimensions: Data completeness, methodological logic, and rigor of the evidence chain. By supplementing baseline data on lipid parameters in the patient cohort, clarifying the rationale for gene screening while expanding the analytical scope, and strengthening the association between hypotheses and supporting evidence, the reliability and scientific validity of the study’s conclusions can be significantly enhanced. This would enable a more accurate reflection of the complex interplay between lipid metabolism and immune regulation in esophageal cancer. LDL: Low-density lipoprotein; TG: Triglyceride; TC: Total cholesterol.

ACKNOWLEDGEMENTS

We are deeply grateful to Professor Chaoming Zhou and Professor Caiwen Duan for their guidance on this Letter. As authoritative experts in oncology and metabolomics, their insightful suggestions have significantly enhanced the academic rigor and professional depth of this manuscript.