Abstract:

Colorectal cancer (CRC) is a prevalent and challenging type of cancer worldwide. Recent research has focused intensively on understanding the molecular and pathological mechanisms of CRC because of the poor prognosis associated with its treatment. The tumor microenvironment (TME) is crucial in tumor progression and has been the subject of extensive investigation. Metabolic reprogramming has become a central focus in cancer research, with numerous studies emphasizing its importance in CRC. Specifically, the reprogramming of fatty acids has been found to alter the energy and nutrient composition within the tumor microenvironment, affecting the complex interaction between immune cells, especially macrophages and T cells, and associated immune factors. This disruption can influence the tumor's ability to evade immune surveillance. Our in-depth analysis highlights the role of lipid metabolism processes in shaping the immune microenvironment of colorectal cancer tumors, revealing the regulatory impact of fatty acid metabolism on CRC development. The potential impact of this research on improving CRC treatment is significant, underscoring the importance of contribution to this field.

References:

[1].   Chen, X., Ma, Z., Yi, Z., Wu, E., Shang, Z., Tuo, B., and Liu, X., 2024, The Effects of Metabolism on the Immune Microenvironment in Colorectal Cancer, Cell Death Discovery, 10(1), 118. https://doi.org/10.1038/s41420-024-01865-z

[2].   Marcellinaro, R., Spoletini, D., Grieco, M., Avella, P., Cappuccio, M., Troiano, R., and Carlini, M., 2023, Colorectal Cancer: Current Updates and Future Perspectives. Journal of Clinical Medicine, 13(1), 40. https://doi.org/10.3390/jcm13010040

[3].   Chung, R. Y. N., Tsoi, K. K., Kyaw, M. H., Lui, A. R., Lai, F. T., and Sung, J. J. Y., 2019, A Population-Based Age-Period-Cohort Study of Colorectal Cancer Incidence Comparing Asia Against the West. Cancer Epidemiology, 59, 29-36. https://doi.org/10.1016/j.canep.2019.01.007

[4].   Zhang, S., Lv, K., Liu, Z., Zhao, R., and Li, F.,2024, Fatty Acid Metabolism of Immune Cells: A New Target of Tumour Immunotherapy. Cell Death Discovery, 10(1), 39. https://doi.org/10.1038/s41420-024-01807-9

[5].   Liberti, M. V., and Locasale, J. W., 2016, The Warburg Effect: How Does it Benefit Cancer Cells? Trends in Biochemical Sciences, 41(3), 211-218. https://doi.org/10.1016/j.tibs.2015.12.001

[6].   Akter, R., Awais, M., Boopathi, V., Ahn, J. C., Yang, D. C., Kang, S. C., and Jung, S. K., 2024, Inversion of the Warburg Effect: Unraveling the Metabolic Nexus between Obesity and Cancer. ACS Pharmacology & Translational Science, 7(3), 560-569. https://doi.org/10.1021/acsptsci.3c00301

[7].   Iranpanah ,A., Majnooni, M. B., Biganeh, H., Amirian, R., Rastegari-Pouyani, M., Filosa, R., Cheang, W. S, Fakhri, S., and Khan, H., 2024, Exploiting New Strategies in Combating Head and Neck Carcinoma: A Comprehensive Review on Phytochemical Approaches Passing Through PI3K/Akt/mTOR Signaling Pathway. Phytother Res, Jul;38(7):3736-3762. https://doi.org/10.1002/ptr.8228

[8].   Koundouros, N., and Poulogiannis, G., 2020, Reprogramming of Fatty Acid Metabolism in Cancer. British Journal of Cancer, 122(1), 4-22. https://doi.org/10.1038/s41416-019-0650-z

[9].   Shao, N., Qiu, H., Liu, J., Xiao, D., Zhao, J., Chen, C., and Xu, L., 2024, Targeting Lipid Metabolism of Macrophages: A New Strategy for Tumor Therapy. Journal of Advanced Research, S2090-1232. https://doi.org/10.1016/j.jare.2024.02.009

[10].  Wu, Y., Pu, X., Wang, X., and Xu, M., 2024, Reprogramming of Lipid Metabolism in the Tumor Microenvironment: A Strategy for Tumor Immunotherapy. Lipids in Health and Disease, 23(1), 35. https://doi.org/10.1186/s12944-024-02024-0

[11].  Chen, X., Chen, S., and Yu, D., 2020, Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance. Metabolites, 10(7), 289. https://doi.org/10.3390/metabo10070289

[12].  Luo, Y., Wang, H., Liu, B., and Wei, J., 2022, Fatty Acid Metabolism and Cancer Immunotherapy. Current Oncology Reports, 24(5), 659-670. https://doi.org/10.1007/s11912-022-01223-1

[13].  Liang, X. H., Chen, X. Y., Yan, Y., Cheng, A. Y., Lin, J. Y., Jiang, Y. X., and Luan, X., 2024, Targeting Metabolism to Enhance Immunotherapy Within Tumor Microenvironment. Acta Pharmacologica Sinica, 1-12. https://doi.org/10.1038/s41401-024-01304-w

[14].  Jin, J., Byun, J. K., Choi, Y. K., and Park, K. G., 2023, Targeting Glutamine Metabolism as a Therapeutic Strategy for Cancer. Experimental & Molecular Medicine, 55(4), 706-715. https://doi.org/10.1038/s12276-023-00971-9

[15].  Pascual, G., Majem, B., and Benitah, S. A., 2024, Targeting Lipid Metabolism in Cancer Metastasis. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1879(1), 189051. https://doi.org/10.1016/j.bbcan.2023.189051

[16].  Wang, R., Yan, Q., Liu, X., and Wu, J., 2024. Unraveling Lipid Metabolism Reprogramming for Overcoming Drug Resistance in Melanoma. Biochemical Pharmacology, 116122. https://doi.org/10.1016/j.bcp.2024.116122

[17].  Gupta, A., Das, D., and Taneja, R., 2024, Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors. Cancers, 16(7), 1313. https://doi.org/10.3390/cancers16071313

[18].  Krauß, D., Fari, O., and Sibilia, M., 2022, Lipid Metabolism Interplay in CRC—An Update. Metabolites, 12(3), 213. https://doi.org/10.3390/metabo12030213

[19].  Endo, Y., Kanno, T., and Nakajima, T., 2022, Fatty Acid Metabolism in T-cell Function and Differentiation. International Immunology, 34(11), 579-587. https://doi.org/10.1093/intimm/dxac025

[20].  Liu, X. F., Shao, J. H., Liao, Y. T., Wang, L. N., Jia, Y., Dong, P. J., and Zhang, X., 2023, Regulation of Short-Chain Fatty Acids in the Immune System. Frontiers in Immunology, 14, 1186892. https://doi.org/10.3389/fimmu.2023.1186892

[21].  Kim, J. H., Kim, B. S., and Lee, S. K., 2020, Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy. Immune Network, 20(1). https://doi.org/10.4110/in.2020.20.e4

[22].  Zhang, Y., Kurupati, R., Liu, L., Zhou, X. Y., Zhang, G., Hudaihed, A., and Ertl, H. C., 2017, Enhancing CD8+ T Cell Fatty Acid Catabolism Within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Cancer cell, 32(3), 377-391. https://doi.org/10.1016/j.ccell.2017.08.004

[23].  Sun, P., Zhang, X., Wang, R. J., Ma, Q. Y., Xu, L., Wang, Y., and Meng, L. H., 2021, PI3Kα Inhibitor CYH33 Triggers Antitumor Immunity in Murine Breast Cancer by Activating CD8+ T Cells and Promoting Fatty Acid Metabolism. Journal for Immunotherapy of Cancer, 9(8). https://doi.org/10.1136/jitc-2021-003093

[24].  Wang, Z., Little, N., Chen, J., Lambesis, K. T., Le, K. T., Han, W., and Lu, J., 2021, Immunogenic Camptothesome Nanovesicles Comprising Sphingomyelin-Derived Camptothecin Bilayers for Safe and Synergistic Cancer Immunochemotherapy. Nature Nanotechnology, 16(10), 1130-1140. https://doi.org/10.1038/s41565-021-00950-z

[25].  Wu, H., Han, Y., Rodriguez Sillke, Y., Deng, H., Siddiqui, S., Treese, C., and Glauben, R., 2019, Lipid Droplet‐Dependent Fatty Acid Metabolism Controls the Immune Suppressive Phenotype of Tumor‐Associated Macrophages. EMBO Molecular Medicine, 11(11), e10698. https://doi.org/10.15252/emmm.201910698

[26].  Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., and Manning, B. D., 2010, Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1. Molecular cell, 39(2), 171-183. https://doi.org/10.1016/j.molcel.2010.06.022

[27].  Ma, X., Bi, E., Lu, Y., Su, P., Huang, C., Liu, L., and Yi, Q., 2019, Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment. Cell Metabolism, 30(1), 143-156. https://doi.org/10.1016/j.cmet.2019.04.002

[28].  Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., and Jacks, T., 2007, Restoration of p53 Function Leads to Tumour Regression in Vivo. Nature, 445(7128), 661-665. https://doi.org/10.1038/nature05541

[29].  Keerthivasan, S., Aghajani, K., Dose, M., Molinero, L., Khan, M. W., Venkateswaran, V., and Gounari, F., 2014, β-Catenin Promotes Colitis and Colon Cancer Through Imprinting of Proinflammatory Properties in T Cells. Science Translational Medicine, 6(225), 225ra28-225ra28. https://doi.org/10.1126/scitranslmed.3007607

[30].  Yu, F. X., Zhao, B., Panupinthu, N., Jewell, J. L., Lian, I., Wang, L. H., and Guan, K. L., 2012, Regulation of the Hippo-YAP Pathway by G-Protein-Coupled Receptor Signaling. Cell, 150(4), 780-791. https://doi.org/10.1016/j.cell.2012.06.037

[31].  Zhang, D., Shi, R., Xiang, W., Kang, X., Tang, B., Li, C., and Miao, H., 2020, The Agpat4/LPA Axis In Colorectal Cancer Cells Regulates Antitumor Responses Via p38/p65 Signaling in Macrophages. Signal Transduction and Targeted Therapy, 5(1), 24. https://doi.org/10.1038/s41392-020-0117-y

[32].  Chen, J., Zhu, H., Yin, Y., Jia, S., and Luo, X., 2022, Colorectal Cancer: Metabolic Interactions Reshape the Tumor Microenvironment. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1877(5), 188797. https://doi.org/10.1016/j.bbcan.2022.188797

[33].  Wang, Z., Cordova, L. E., Chalasani, P., and Lu, J.,2022, Camptothesome Potentiates PD-L1 Immune Checkpoint Blockade for Improved Metastatic Triple-Negative Breast Cancer Immunochemotherapy. Molecular Pharmaceutics, 19(12), 4665-4674. https://doi.org/10.1016/j.bbcan.2022.188797