Enhancing Colorectal Cancer Immunotherapy: The Pivotal Role of Ferroptosis in Modulating the Tumor Microenvironment
Abstract
:1. Introduction
2. Ferroptosis: Understanding Its Mechanism and Impact
3. Effect of Tumor Microenvironment (TME) on Ferroptosis
4. The Role of Ferroptosis in Immunotherapy for Cancer
5. The Challenges of Immunotherapy in CRC
6. The Role of Ferroptosis in Immunotherapy for CRC
7. Global Research Trends
8. Challenges and Limitations
9. Future Prospect
10. Summary
Author Contributions
Funding
Conflicts of Interest
References
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TME Factor/ Regulator | Mechanism of Impact | Effect on Ferroptosis | Reference Numbers |
---|---|---|---|
Hypoxia | Induction of IRP2 post-translational upregulation<br>- Regulation of iron transporter and storage protein expression | Promotes ferroptosis | [26] |
Carbonic Anhydrase IX (CAIX) | Modulation of the cystine/glutamate antiporter xCT | Prevents ferroptosis | [27,28] |
HIF-1α/lncRNA-PMAN | Regulation of key genes involved in iron metabolism | Protects cancer cells from ferroptosis | [29] |
CBSLR/CBS Signal Axis | Same as above | Protects cancer cells from ferroptosis | [29] |
NCOA4 Expression Reduction | Reduced expression in macrophages, leading to increased ferritin levels and decreased ferroptosis susceptibility | Decreases ferroptosis susceptibility | [22,30] |
Polymeric Nanocarriers | Depleting NADPH, GSH, and Trx to sensitize hypoxic tumor cells to ferroptosis | Sensitizes hypoxic tumor cells to ferroptosis | [31,32] |
Lactate Accumulation | Upregulation of HCAR1 and MCT1 reducing lipid peroxidation | Inhibits ferroptosis | [33] |
Inflammatory Factors | Regulation of ferroptosis through various cancer types and signaling pathways, such as JAK2/STAT3 and RAS-JNK/p38 | May promote or inhibit ferroptosis | [34] |
Non-coding RNAs | Modulation of ferroptosis by targeting key regulators like xCT and GPX4 | Influences cancer progression and ferroptosis | [35] |
CD8 T Cells | Secretion of cytokines like IFNγ inhibiting the expression of SLC3A2 and SLC7A11 | Promotes ferroptosis in tumor cells | [36,37] |
oxLDL and CD36 | Inducing ferroptosis and p38 phosphorylation in CD8+ T cells via CD36-dependent mechanisms | Affects T cell function and antitumor immunity | [40,41,42] |
NK Cells | Cytotoxic effects on tumor cells through perforin, granzyme, and IFNγ release | Enhances NK cell activity and promotes ferroptosis | [42,43] |
Ferroptosis and Immune Response | Release of cytokines and DAMPs without activating antitumor immune responses, inhibiting dendritic cell functions | May not represent an immunogenic cell death form | [44,45] |
Drug/Molecule | Target | Clinical Trial ID | Phase | Combination/Specific Aim | Reference |
---|---|---|---|---|---|
Sulfasalazine | SLC7A11 | NCT06134388 | Phase I | Metastatic CRC | - |
CNSI-Fe (II) | Iron ions | NCT06048367 | Phase I | Advanced solid tumors including CRC | - |
Neratinib | Iron ions | NCT03457896 | Phase II | Combination with Trastuzumab or Cetuximab | - |
Lapatinib | Iron ions | NCT00536809 NCT00574171 NCT01184482 NCT04831528 NCT03418558 | Phase I/II | Combination with various drugs | [102] |
Sorafenib | SLC7A11 | NCT00780169 NCT00869570 NCT00989469 NCT01715441 NCT00826540 NCT01290926 NCT00134069 NCT00865709 NCT00703638 NCT01376453 | Phase I/II | Combination with chemotherapy | [103,104,105,106,107,108] |
Simvastatin | HMGCR | NCT01238094 | Phase I | Combination with XELIRI/FOLFIRI | - |
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Li, Y.; Cheng, X. Enhancing Colorectal Cancer Immunotherapy: The Pivotal Role of Ferroptosis in Modulating the Tumor Microenvironment. Int. J. Mol. Sci. 2024, 25, 9141. https://doi.org/10.3390/ijms25179141
Li Y, Cheng X. Enhancing Colorectal Cancer Immunotherapy: The Pivotal Role of Ferroptosis in Modulating the Tumor Microenvironment. International Journal of Molecular Sciences. 2024; 25(17):9141. https://doi.org/10.3390/ijms25179141
Chicago/Turabian StyleLi, Yanqing, and Xiaofei Cheng. 2024. "Enhancing Colorectal Cancer Immunotherapy: The Pivotal Role of Ferroptosis in Modulating the Tumor Microenvironment" International Journal of Molecular Sciences 25, no. 17: 9141. https://doi.org/10.3390/ijms25179141