The recent study by Qin et al. [
1], titled “CD36 promotes iron accumulation and dysfunction in CD8
+ T cells via the p38-CEBPB-TfR1 axis in early-stage hepatocellular carcinoma,” published in
Clinical and Molecular Hepatology, offers new insights into how CD36 and nuclear factor erythroid-2-related factor 2 (NRF2) are involved in CD8
+ T cell dysfunction during the early phases of hepatocellular carcinoma (HCC). This research challenges the common view that T cell exhaustion mainly happens in advanced HCC, showing instead that CD8
+ T cell problems can begin as early as 6 to 9 weeks in mouse models [
1]. The discovery that CD36 drives iron buildup and lipid peroxidation, and that activating NRF2 can help restore T cell function, has important implications for developing immunotherapies for HCC. This comment aims to emphasize the significance of this study, discuss its limitations, and propose future directions for research.
Qin et al.’s work [
1] discovers that CD36, a scavenger receptor, plays a key role in causing CD8
+ T cell dysfunction through the oxidized low-density lipoprotein-CD36-transferrin receptor 1 (oxLDL-CD36-TFR1) pathway, which leads to iron buildup and lipid peroxidation. Interestingly, blocking CD36 improves the effectiveness of programmed cell death protein 1 (PD-1)-based immunotherapy, reduces levels of inhibitory receptors like PD-1, TIM-3, and TIGIT, and boosts T cell activity. These findings are especially important because HCC remains a tough cancer to treat, with limited success from immune checkpoint inhibitors due to the complex tumor environment [
2]. The combined approach of inhibiting CD36 along with PD-1 could be a promising strategy for therapy. Similar approaches targeting lipid metabolism in T cells have shown benefits in other cancers like melanoma, aligning with Qin et al.’s findings [
3]. What’s more, the link between high levels of CD36 and transferrin receptor 1 (TFR1) in HCC patients, along with poorer outcomes, suggests they could be useful as biomarkers or therapeutic targets.
However, the study mainly uses mouse models (such as subcutaneous tumors and hydrodynamic injections), so more work is needed to see how well these results translate to humans. Human HCC develops in the liver’s specific environment, which has unique metabolic and immune features that might not be fully replicated in these models [
4]. Besides, it’s still unclear whether CD36 has a unique role, since other scavenger receptors like SR-A or LOX-1 might also be involved in lipid peroxidation in T cells.
The finding that activating NRF2 can decrease lipid peroxidation and improve CD8
+ T cell function is particularly interesting. NRF2 is known as a master regulator of oxidative stress and has been widely studied in cancer [
5]; however, Qin et al. [
1] mention that activating NRF2 might help HCC cells survive, aligning with reports that NRF2 activation in tumor cells contributes to resistance to chemotherapy and cancer progression [
6]. While research on NRF2 in tumor immunity is advancing, its dual roles, protecting T cells but possibly aiding tumor growth, are not yet fully understood. The lack of direct experiments on how NRF2 affects HCC cells in this study suggests that further investigation is necessary. Future studies could use T cell-specific NRF2 activators or gene editing tools like CRISPR to clarify its distinct roles in immune cells versus cancer cells, which could guide the creation of safer, more effective therapies.
Despite the significance of Qin et al.’s findings [
1], some issues need further attention. First, the statistical methods are not clearly described, with missing details on sample sizes,
P-values, or confounding variables in human data, which could impact reproducibility. Second, the way “early” and “late” HCC are defined, based on tumor size and time (6–9 weeks vs. 11–13 weeks), lacks molecular or pathological markers, so it’s unclear how biologically relevant this staging is. Also, there are repeated data points across several pages (e.g., pages 2, 6, and 8), which may indicate reporting errors that need clarification. To push this promising research forward, we recommend the following steps:
First, validate findings in more relevant models, such as orthotopic HCC models or patient-derived xenografts, to better reflect the human liver tumor microenvironment. Second, investigate whether CD36’s role is unique by conducting knockout experiments targeting other scavenger receptors like SR-A. Third, explore the dual role of NRF2 by designing experiments that distinguish its effects in T cells vs. tumor cells to develop targeted therapies. Fourth, improve statistical rigor by providing detailed methods, including sample sizes and adjustments for confounders, to strengthen confidence in the results.
In summary, Qin et al.’s study [
1] offers a fresh perspective on CD8
+ T cell impairment in early HCC, emphasizing the importance of CD36 and NRF2 in immune response regulation. While there are limitations regarding model systems and statistical reporting, their findings align with the growing interest in targeting lipid metabolism and oxidative stress for cancer immunotherapy. Further research will hopefully clarify the potential of CD36 and NRF2 as therapeutic targets and guide clinical strategies for better HCC treatment.
FOOTNOTES
-
Authors’ contribution
HW and XS conceived the topic and wrote the first draft. YK and KX collected data and revised the manuscript. All authors approved the final version.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
nuclear factor erythroid-2-related factor 2
oxidized low-density lipoprotein-CD36-transferrin receptor 1
programmed cell death protein 1
REFERENCES
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- 3. Ma X, Xiao L, Liu L, Ye L, Su P, Bi E, et al. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab 2021;33:1001-1012.e5.
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- 6. Gan L, Wang W, Jiang J, Tian K, Liu W, Cao Z. Dual role of Nrf2 signaling in hepatocellular carcinoma: promoting development, immune evasion, and therapeutic challenges. Front Immunol 2024;15:1429836.
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