Hepatocellular carcinoma (HCC) remains a formidable challenge in oncology, particularly due to the immunosuppressive tumor microenvironment (TME) that fosters T cell dysfunction [
1]. The current study by Qin et al. [
2] sheds new light on a previously unidentified pathway driving CD8+ T cell exhaustion, elucidating the role of CD36 in iron and lipid metabolism in early-stage HCC. The authors provide a compelling mechanistic framework linking metabolic dysregulation to impaired anti-tumor immunity, offering a potential avenue for therapeutic intervention.
CD8+ T cells are crucial effectors of anti-tumor immunity. However, in early-stage HCC, tumor-infiltrating CD8+ T cells progressively acquire an exhausted phenotype characterized by diminished effector functions [
3]. In this study, the authors demonstrate that CD8+ T cell exhaustion increases during HCC progression, exacerbated by excessive iron accumulation, and identify CD36 as a key driver of this metabolic disruption [
2].
Iron overload in CD8+ T cells accelerates the formation of lipid peroxides, a process that contributes to ferroptosis—a form of iron-dependent cell death [
4]. However, rather than inducing outright cell death, the study suggests that lipid peroxidation fosters a state of exhaustion in CD8+ T cells [
2]. This exhaustion is marked by increased expression of immunosuppressive molecules PD-1 and TIM-3 as well as decreased cytotoxic cytokines production including TNFα, Perforin, and Granzyme B, ultimately impairing the ability of these immune cells to mount an effective anti-tumor response (
Fig. 1).
CD36, a scavenger receptor involved in lipid metabolism [
5] has been previously shown to mediate fatty acid uptake by intratumoral CD8+ T cells, inducing lipid peroxidation and ferroptosis, which reduces cytotoxic function and impairs antitumor activity [
6]. In the current study, CD36 is demonstrated to facilitate iron accumulation in CD8+ T cells by upregulating transferrin receptor 1 (TfR1), the primary iron uptake protein. Mechanistically, upon CD36-driven oxidized low-density lipoprotein (oxLDL) uptake, the p38 MAPK pathway is activated. This leads to phosphorylation of p38 (p-p38), triggering the C/EBPβ and C/EBPδ transcription factors. The author went on to show that C/EBPβ plays a dominant role in TfR1 regulation, by binding directly to the TFRC promoter to increase its transcription. This leads to increased TFRC and hence intracellular ferrous iron, which, in turn, exacerbates lipid peroxidation and compromises T cell effector functions (
Fig. 1) [
2]. The mechanistic insights provided underscore the intricate crosstalk between lipid and iron metabolism in shaping the immune landscape of early-stage HCC.
Notably, the authors demonstrate that deletion of CD36 or the use of the specific inhibitor SSO mitigates these effects, preventing excessive iron accumulation and preserving T cell function. These findings position CD36 as a crucial metabolic checkpoint in CD8+ T cells, implicating its role as a potential therapeutic target in HCC immunotherapy.
In addition to the CD36-dependent mechanisms, the activation of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway offers a protective mechanism against the metabolic disruptions caused by iron accumulation and lipid peroxidation in CD8+ T cells. NRF2 is a key regulator of cellular responses to oxidative stress, and its activation helps mitigate the toxic effects of lipid peroxides and iron-induced damage [
7]. NRF2 regulates the expression of various antioxidant genes and enzymes, promoting the cellular repair of oxidative damage and protecting against ferroptosis [
8].
This study suggests that NRF2 activation in CD8+ T cells can effectively preserve their effector functions despite the metabolic challenges posed by excessive iron and lipid peroxidation [
2]. By enhancing the antioxidant response, NRF2 reduces lipid peroxidation, which is otherwise exacerbated by high iron levels and the presence of oxLDL. This mitigation of oxidative damage allows CD8+ T cells to retain their cytotoxic capabilities, such as the production of IFNγ and TNFα, which are essential for effective anti-tumor immunity (
Fig. 1). Furthermore, NRF2 activation also reduces TfR1 expression, which limits additional iron uptake and prevents further exacerbation of ferroptosis. These findings underscore the therapeutic potential of NRF2-targeted therapies to counteract metabolic dysfunction in T cells, demonstrated by the authors where overexpression of activated NRF2 in intratumoral CD8+ T cells effectively rescue its anti-tumor function and inhibit tumor growth [
2].
The implications of this work extend beyond the mechanistic understanding of CD8+ T cell exhaustion in HCC. Current immunotherapies in HCC, mainly with the use of immune checkpoint inhibitors, have shown limited efficacy in HCC, particularly with limited data from early-stage disease [
9]. The metabolic dysfunction outlined in this study suggests that targeting CD36 or augmenting NRF2 activity could enhance the efficacy of existing immunotherapies by restoring the functional capacity of tumor-infiltrating CD8+ T cells.
Furthermore, the study underscores the importance of metabolic interventions in modulating the immune response. While immune checkpoint blockade has traditionally been the focus of cancer immunotherapy, this work highlights the potential of metabolic reprogramming as an adjunctive strategy to reinvigorate exhausted T cells. Combining metabolic interventions with checkpoint inhibitors or adoptive T cell therapies could provide a more comprehensive approach to enhancing anti-tumor immunity.
Several important questions remain. First, while the study convincingly demonstrates the role of CD36 in promoting iron accumulation and lipid peroxidation, it remains to be seen whether pharmacological inhibition of CD36 can effectively restore T cell function in patients. Additionally, the potential off-target effects of NRF2 activation warrant further investigation, particularly in the context of tumor biology, where NRF2 has been implicated in both tumor suppression and progression [
10].
Another critical avenue for future research is the exploration of how CD36-mediated metabolic dysfunction influences other immune cell subsets within the HCC TME. For instance, given that iron metabolism plays a pivotal role in macrophage polarization and functions [
11], understanding the broader immunometabolic landscape of HCC could unveil additional therapeutic targets.
This study provides mechanistic insights into how CD36-driven iron accumulation and lipid peroxidation contribute to CD8+ T cell exhaustion in early-stage HCC. By elucidating the oxLDL-p38-CEBPB-TfR1 axis, the authors uncover a previously unrecognized mechanism linking metabolic dysregulation to impaired anti-tumor immunity. The activation of NRF2 and inhibition of CD36 represent promising strategies for enhancing immunotherapy outcomes in HCC. As the field of cancer immunometabolism evolves, combining metabolic interventions with immune-based therapies may pave the way for more effective treatments for HCC and other solid tumors.
FOOTNOTES
-
Acknowledgements
This work was supported by the National Medical Research Council (NMRC), Singapore (reference number: CIRG22jul-0025, NMRC/OFLCG/003/2018) and National Research Foundation, Singapore (ref number: NRF-CRP26-2021-0005).
-
Conflicts of Interest
The author has no conflicts to disclose.
Figure 1.Mechanism of CD36-driven CD8+ T cell dysfunction in early-stage hepatocellular carcinoma (HCC). Schematic diagram illustrating the mechanism by which CD36 induces iron accumulation, lipid peroxidation and reactive oxygen species (ROS) production in CD8+ T cells within the tumor microenvironment of early-stage HCC. Oxidized low-density lipoproteins (oxLDL) is taken up by CD36, triggering the p38 MAPK pathway. This leads to phosphorylation of p38 (p-p38) and activation of C/EBPβ, which enhances the transcription of transferrin receptor 1 (TfR1). TfR1 then translocates to the cell membrane, facilitating increased iron uptake. The resulting iron accumulation further promotes lipid peroxidation and ROS production, creating a feedback loop that exacerbates CD8+ T cell dysfunction, leading to exhaustion and impaired anti-tumor immunity.
Abbreviations
nuclear factor erythroid 2-related factor 2
oxidized low-density lipoprotein
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Citations
Citations to this article as recorded by
- Correspondence to editorial on “CD36 Promotes iron accumulation and dysfunction in CD8+ T cells via the p38-CEBPB-TfR1 axis in early-stage hepatocellular carcinoma”
Yifei Qin, Peng Lin, Huijie Bian, Zhi-Nan Chen, Jiao Wu
Clinical and Molecular Hepatology.2026; 32(1): e75. CrossRef
