Dear Editor,
We would like to express our sincere gratitude to Dr. Valerie Chew for her interest in our previous study “CD36 promotes iron accumulation and dysfunction in CD8
+ T cells via the p38-CEBPB-TfR1 axis in early-stage hepatocellular carcinoma” [
1]. Her editorial provides a clear and concise summary of our work, which uncovered a previously unknown mechanism regulating CD8
+ T cell dysfunction [
2]. Specifically, it explains how CD36 promotes iron accumulation and lipid peroxidation in CD8
+ T cells by activating the oxLDL-p38-CEBPB-TfR1 axis. In addition, the editorial offers valuable guidance for our future research and insightful perspectives, which help us better understand the context and scope of our findings.
In our previous research, we detected a pronounced infiltration of CD8+ T cells in early-stage hepatocellular carcinoma (HCC). However, these cells exhibited heightened expression of molecules associated with exhaustion, as well as the accumulation of iron and lipid oxidation products. Our findings indicated that elevated iron levels can promote CD8+ T cell exhaustion and induce ferroptosis within these cells. CD36, a key regulator of lipid metabolism, plays a pivotal role in influencing the fate of CD8+ T cell exhaustion in the HCC tumor microenvironment (TME). Specifically, we uncovered that CD36 regulates TfR1 expression via the oxLDL-p38-CEBPB axis, thereby contributing to iron accumulation. In addition, we discovered that a constitutively active form of NRF2 can protect CD8+ T cells from dysfunction. In summary, our study elucidates a novel mechanism by which CD36 regulates CD8+ T cell dysfunction in the early HCC TME and provides potential new therapeutic avenues for restoring T cell function.
Metabolic dysregulation within the TME significantly impairs the anti-tumor function of CD8
+ T cells [
3]. Emerging evidence suggests that CD36 plays a crucial role in modulating T cell function within this context. Specifically, CD36 promotes the uptake of fatty acids by tumor-infiltrating CD8
+ T cells, leading to lipid peroxidation and ferroptosis, thereby suppressing the cytotoxic activity of these T cells. Notably, inhibiting CD36 or blocking lipid peroxidation can significantly restore the anti-tumor activity of CD8
+ T cells and enhance the efficacy of anti-PD-1 immunotherapy [
4]. Furthermore, CD36
+ cancer-associated fibroblasts (CAFs) contribute to an immunosuppressive microenvironment in HCC by secreting macrophage migration inhibitory factors. Inhibition of CD36, such as with the use of SSO, has been shown to restore anti-tumor T cell responses in HCC models [
5]. Additionally, CD36 activates the PPAR-β signaling pathway, enhancing the mitochondrial adaptability of regulatory T cells (Tregs) and thereby strengthening their immunosuppressive function within tumors. Targeting CD36 may thus reduce the immunosuppressive effects of Tregs and restore the anti-tumor function of T cells [
6]. Our study further elucidates that CD36 mediates the induction of iron accumulation in CD8
+ T cells within the iron-enriched TME of early-stage HCC. This process contributes to lipid peroxidation and subsequent dysfunction of CD8
+ T cells.
These findings reinforce the role of CD36 in CD8+ T cell dysfunction and indicate that pharmacologically inhibiting CD36 holds promise for restoring T cell function. Although the exhaustion of tumor-infiltrating CD8+ T cells show up even at the early stages of tumorigenesis, its severity increases with tumor progression. The enhanced uptake of iron by tumor-infiltrating CD8+ T cells from the iron-enriched TME leads to increased lipid peroxidation and further compromises the anti-tumor functions of CD8+ T cells. Therefore, we speculate that intervening with CD36 at an early stage of HCC development may more effectively rescue the anti-tumor function of CD8+ T cells. Moreover, further validation is necessary to elucidate the effects of CD36 inhibitors on CD8+ T cells in HCC patients. Additionally, the efficacy and mechanisms of action of CD36 inhibitors in different types of tumors warrant further investigation.
In addition to the role in CD8
+ T cells, CD36-mediated metabolic dysfunction significantly impacts other immune cell subsets within the HCC TME, particularly in macrophage polarization and function. Iron metabolism is a key regulator of macrophage polarization, as it can inhibit STAT1 activation, thereby reducing M1-type macrophage polarization [
7]. Additionally, CD36 regulates macrophage function through lipid metabolism in the TME. In patients with liver metastases, high expression of CD36 is associated with the infiltration of protumoral M2-type macrophages, creating a highly immunosuppressive TME [
8]. Future research should delve into the mechanisms by which CD36 regulates macrophage polarization and function through iron metabolism, as well as the broader role of CD36 in lipid metabolism and its impact on the TME.
The transcription factor NRF2 exhibits a dual role in tumors. On one hand, NRF2 functions as a “gatekeeper” by alleviating oxidative stress, maintaining cellular homeostasis, and supporting overall cell health, thereby inhibiting tumorigenesis. On the other hand, its overexpression in cancer cells endows them with a survival advantage and resistance to treatment [
9]. NRF2 also regulates ferritin synthesis and degradation, preventing the accumulation of labile iron pools through three signaling pathways [
10]. While our study demonstrates that a constitutively active form of NRF2 enhances CD8
+ T cell function, significant challenges remain regarding how NRF2 balances iron signaling in iron-enriched HCC TME and the potential off-target toxicity associated with the activated form of NRF2. These issues represent critical areas for future research. Moving forward, our research will focus on two main directions. First, we plan to explore the potential of incorporating a constitutively active form of NRF2 into CAR-T cells. This innovative approach aims to develop CAR-T cells that are resistant to ferroptosis, thereby enhancing their anti-tumor efficacy. By leveraging the antioxidant and anti-ferroptotic properties of NRF2, we hope to improve the durability and effectiveness of CAR-T cell therapy, particularly in the oxidative stressrich TME. Second, future research should prioritize the development of targeted NRF2 activators that can specifically enhance NRF2 activity in T cells without promoting tumor cell proliferation. This strategy aims to provide a more controlled and therapeutic application of NRF2 activation, minimizing the risk of unintended consequences. By addressing these challenges, we hope to advance the clinical application of NRF2-based therapies and improve outcomes for patients with HCC and other cancers.
As a novel form of cell death, ferroptosis has been implicated in the pathogenesis of various diseases, including pulmonary fibrosis, neurodegenerative diseases such as Parkinson’s disease and glaucoma, cardiovascular diseases like myocardial infarction and heart failure, autoimmune diseases such as systemic lupus erythematosus and inflammatory bowel disease, and metabolic disorders like diabetes [
11,
12]. Additionally, it plays a role in acute organ injuries, including ischemia/reperfusion injury in the heart, liver, kidney, and lung [
13]. These findings highlight the broad relevance of ferroptosis in disease pathology and suggest that targeting ferroptosis may offer therapeutic potential across multiple conditions. Our previous research indicates that type II alveolar epithelial cells undergo ferroptosis during the progression of pulmonary fibrosis, thereby exacerbating its development [
14]. Specifically, the activation of NRF2 has been shown to inhibit ferroptosis in several models. By enhancing the expression of antioxidant enzymes such as GPX4 and HO-1, NRF2 activation can mitigate iron-dependent lipid peroxidation, a hallmark of ferroptosis [
15]. This suggests that targeting NRF2 to inhibit ferroptosis may be a promising approach to protect normal cells from ferroptosis-induced damage, thereby reducing organ injury in diseases such as pulmonary fibrosis. Further research is warranted to elucidate the specific mechanisms and therapeutic potential of NRF2 activation in diverse disease contexts. In summary, while the clinical application of NRF2 activators remains a promising yet challenging area, we believe that targeted approaches and innovative cell engineering strategies can overcome current limitations.
FOOTNOTES
-
Authors’ contribution
Manuscript drafting: Yifei Qin, Jiao Wu. Revision and supervision: Zhi-Nan Chen, Huijie Bian, Peng Lin. Final approval: All authors.
-
Acknowledgements
This work was supported by the National Natural Science Foundation of China (82270078), Top Team in Strategy of Sanqin Talent Special Support Program of Shaanxi Province, Youth Innovation Team of Shaanxi Province.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
cancer-associated fibroblasts
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