Overcoming Metabolic Challenges in the Tumor Microenvironment: Current Solutions
Tolulope Bolarinwa, Irene Sagay, Opeoluwa Oluwanifemi Akomolafe, Ajao, Ebenezer Taiwo, Sandra Oparah
Abstract
The tumor microenvironment (TME) presents significant metabolic challenges, including hypoxia, acidosis, nutrient deprivation, and metabolic flexibility, which contribute to tumor progression and resistance to therapy. This review explores current solutions to these challenges, such as hypoxia-activated prodrugs, buffer therapy, proton pump inhibitors, amino acid supplementation, and inhibitors of metabolic flexibility. The implications of these solutions for improving cancer treatment outcomes are profound, highlighting the importance of targeting the unique metabolic characteristics of the TME. Additionally, the review discusses the potential of emerging technologies, combination therapies, and personalized medicine to revolutionize cancer therapy. Continued advancements in cancer metabolism research hold great promise for developing novel therapeutic strategies that can overcome the limitations of current treatments and provide better outcomes for cancer patients.
Keywords
Tumor Microenvironment
Cancer Metabolism
Hypoxia
Acidosis
Metabolic
References
Bogdanov, A., Bogdanov, A., Chubenko, V., Volkov, N., Moiseenko, F., & Moiseyenko, V.
(2022). Tumor acidity: From hallmark of cancer to target of treatment. Frontiers in
Oncology, 12, 979154.
Chen, Z., Han, F., Du, Y., Shi, H., & Zhou, W. (2023). Hypoxic microenvironment in cancer:
molecular mechanisms and therapeutic interventions. Signal transduction and targeted
therapy, 8(1), 70.
Comito, G., Ippolito, L., Chiarugi, P., & Cirri, P. (2020). Nutritional exchanges within tumor
microenvironment: impact for cancer aggressiveness. Frontiers in Oncology, 10, 396.
Cozene, B., Sadanandan, N., Gonzales-Portillo, B., Saft, M., Cho, J., Park, Y. J., & Borlongan,
C. V. (2020). An extra breath of fresh air: hyperbaric oxygenation as a stroke
therapeutic. Biomolecules, 10(9), 1279.
Elebiyo, T. C., Rotimi, D., Evbuomwan, I. O., Maimako, R. F., Iyobhebhe, M., Ojo, O. A., . .
. Adeyemi, O. S. (2022). Reassessing vascular endothelial growth factor (VEGF) in
anti-angiogenic cancer therapy. Cancer Treatment and Research Communications, 32,
Eniafe, J., & Jiang, S. (2021). The functional roles of TCA cycle metabolites in cancer.
Oncogene, 40(19), 3351-3363.
Fendt, S.-M., Frezza, C., & Erez, A. (2020). Targeting metabolic plasticity and flexibility
dynamics for cancer therapy. Cancer discovery, 10(12), 1797-1807.
Gambardella, V., Tarazona, N., Cejalvo, J. M., Lombardi, P., Huerta, M., Roselló, S., . . .
Cervantes, A. (2020). Personalized medicine: recent progress in cancer therapy.
Cancers, 12(4), 1009.
Goul, C., Peruzzo, R., & Zoncu, R. (2023). The molecular basis of nutrient sensing and
signalling by mTORC1 in metabolism regulation and disease. Nature reviews
Molecular cell biology, 24(12), 857-875.
Hapke, R. Y., & Haake, S. M. (2020). Hypoxia-induced epithelial to mesenchymal transition
in cancer. Cancer letters, 487, 10-20.
Huang, C. K., Sun, Y., Lv, L., & Ping, Y. (2022). ENO1 and Cancer. Molecular Therapy-
Oncolytics, 24, 288-298.
Huang, Y., Sun, G., Sun, X., Li, F., Zhao, L., Zhong, R., & Peng, Y. (2020). The potential of
lonidamine in combination with chemotherapy and physical therapy in cancer
treatment. Cancers, 12(11), 3332.
Jacquet, P., & Stéphanou, A. (2022). Searching for the metabolic signature of cancer: A review
from Warburg’s time to now. Biomolecules, 12(10), 1412.
Jaworska, M., Szczud?o, J., Pietrzyk, A., Shah, J., Trojan, S. E., Ostrowska, B., & Kocemba-
Pilarczyk, K. A. (2023). The Warburg effect: a score for many instruments in the
concert of cancer and cancer niche cells. Pharmacological Reports, 75(4), 876-890.
Keerthana, C. K., Rayginia, T. P., Shifana, S. C., Anto, N. P., Kalimuthu, K., Isakov, N., &
Anto, R. J. (2023). The role of AMPK in cancer metabolism and its impact on the
immunomodulation of the tumor microenvironment. Frontiers in Immunology, 14,
Kocianova, E., Piatrikova, V., & Golias, T. (2022). Revisiting the Warburg effect with focus
on lactate. Cancers, 14(24), 6028.
Koltai, T. (2022). The complex relationship between multiple drug resistance and the tumor
pH gradient: a review. Cancer Drug Resistance, 5(2), 277.
Korsakova, L., Krasko, J. A., & Stankevicius, E. (2021). Metabolic-targeted combination
therapy with dichloroacetate and metformin suppresses glioblastoma cell line growth
in vitro and in vivo. in vivo, 35(1), 341-348.
Liu, G. Y., & Sabatini, D. M. (2020). mTOR at the nexus of nutrition, growth, ageing and
disease. Nature reviews Molecular cell biology, 21(4), 183-203.
Martí i Líndez, A.-A., & Reith, W. (2021). Arginine-dependent immune responses. Cellular
and molecular life sciences, 78(13), 5303-5324.
Martínez-Reyes, I., & Chandel, N. S. (2021). Cancer metabolism: looking forward. Nature
Reviews Cancer, 21(10), 669-680.
Mirabile, A., Rivoltini, L., Daveri, E., Vernieri, C., Mele, R., Porcu, L., . . . Cascinu, S. (2020).
Metabolism and Immune Modulation in patients with solid tumors: systematic review
of preclinical and clinical evidence. Cancers, 12(5), 1153.
Moindjie, H., Rodrigues-Ferreira, S., & Nahmias, C. (2021). Mitochondrial metabolism in
carcinogenesis and cancer therapy. Cancers, 13(13), 3311.
Neophytou, C. M., Panagi, M., Stylianopoulos, T., & Papageorgis, P. (2021). The role of tumor
microenvironment in cancer metastasis: Molecular mechanisms and therapeutic
opportunities. Cancers, 13(9), 2053.
Pan, Y., Liu, L., Mou, X., & Cai, Y. (2023). Nanomedicine strategies in conquering and
utilizing the cancer hypoxia environment. ACS nano, 17(21), 20875-20924.
Robles-Flores, M., Moreno-Londoño, A. P., & Castañeda-Patlán, M. C. (2021). Signaling
pathways involved in nutrient sensing control in cancer stem cells: an overview.
Frontiers in Endocrinology, 12, 627745.
Safrhansova, L., Hlozkova, K., & Starkova, J. (2022). Targeting amino acid metabolism in
cancer. International review of cell and molecular biology, 373, 37-79.
Selvakumar, S. C., Preethi, K. A., Ross, K., Tusubira, D., Khan, M. W. A., Mani, P., . . . Sekar,
D. (2022). CRISPR/Cas9 and next generation sequencing in the personalized treatment
of Cancer. Molecular cancer, 21(1), 83.
Sun, N.-Y., & Yang, M.-H. (2020). Metabolic reprogramming and epithelial-mesenchymal
plasticity: opportunities and challenges for cancer therapy. Frontiers in Oncology, 10,
Tanabe, A., & Sahara, H. (2020). The metabolic heterogeneity and flexibility of cancer stem
cells. Cancers, 12(10), 2780.
Tsilingiris, D., Tzeravini, E., Koliaki, C., Dalamaga, M., & Kokkinos, A. (2021). The role of
mitochondrial adaptation and metabolic flexibility in the pathophysiology of obesity
and insulin resistance: an updated overview. Current Obesity Reports, 10, 191-213.
Vaupel, P., & Multhoff, G. (2021). Revisiting the Warburg effect: historical dogma versus
current understanding. The Journal of physiology, 599(6), 1745-1757.
Wang, B., Zhao, Q., Zhang, Y., Liu, Z., Zheng, Z., Liu, S., . . . Jiang, X. (2021). Targeting
hypoxia in the tumor microenvironment: a potential strategy to improve cancer
immunotherapy. Journal of Experimental & Clinical Cancer Research, 40, 1-16.
Wang, R. C., & Wang, Z. (2023). Precision medicine: disease subtyping and tailored treatment.
Cancers, 15(15), 3837.
Zheng, X., Fan, H., Liu, Y., Wei, Z., Li, X., Wang, A., . . . Lu, Y. (2022). Hypoxia boosts
aerobic glycolysis in carcinoma: a complex process for tumour development. Current
Molecular Pharmacology, 15(3), 487-501.
Zhuo, C., Zhang, J., Lee, J.-H., Jiao, J., Cheng, D., Liu, L., . . . Li, M. (2021). Spatiotemporal
control of CRISPR/Cas9 gene editing. Signal transduction and targeted therapy, 6(1),
Zou, Z., Tao, T., Li, H., & Zhu, X. (2020). mTOR signaling pathway and mTOR inhibitors in
cancer: progress and challenges. Cell & bioscience, 10(1), 31.
(2022). Tumor acidity: From hallmark of cancer to target of treatment. Frontiers in
Oncology, 12, 979154.
Chen, Z., Han, F., Du, Y., Shi, H., & Zhou, W. (2023). Hypoxic microenvironment in cancer:
molecular mechanisms and therapeutic interventions. Signal transduction and targeted
therapy, 8(1), 70.
Comito, G., Ippolito, L., Chiarugi, P., & Cirri, P. (2020). Nutritional exchanges within tumor
microenvironment: impact for cancer aggressiveness. Frontiers in Oncology, 10, 396.
Cozene, B., Sadanandan, N., Gonzales-Portillo, B., Saft, M., Cho, J., Park, Y. J., & Borlongan,
C. V. (2020). An extra breath of fresh air: hyperbaric oxygenation as a stroke
therapeutic. Biomolecules, 10(9), 1279.
Elebiyo, T. C., Rotimi, D., Evbuomwan, I. O., Maimako, R. F., Iyobhebhe, M., Ojo, O. A., . .
. Adeyemi, O. S. (2022). Reassessing vascular endothelial growth factor (VEGF) in
anti-angiogenic cancer therapy. Cancer Treatment and Research Communications, 32,
Eniafe, J., & Jiang, S. (2021). The functional roles of TCA cycle metabolites in cancer.
Oncogene, 40(19), 3351-3363.
Fendt, S.-M., Frezza, C., & Erez, A. (2020). Targeting metabolic plasticity and flexibility
dynamics for cancer therapy. Cancer discovery, 10(12), 1797-1807.
Gambardella, V., Tarazona, N., Cejalvo, J. M., Lombardi, P., Huerta, M., Roselló, S., . . .
Cervantes, A. (2020). Personalized medicine: recent progress in cancer therapy.
Cancers, 12(4), 1009.
Goul, C., Peruzzo, R., & Zoncu, R. (2023). The molecular basis of nutrient sensing and
signalling by mTORC1 in metabolism regulation and disease. Nature reviews
Molecular cell biology, 24(12), 857-875.
Hapke, R. Y., & Haake, S. M. (2020). Hypoxia-induced epithelial to mesenchymal transition
in cancer. Cancer letters, 487, 10-20.
Huang, C. K., Sun, Y., Lv, L., & Ping, Y. (2022). ENO1 and Cancer. Molecular Therapy-
Oncolytics, 24, 288-298.
Huang, Y., Sun, G., Sun, X., Li, F., Zhao, L., Zhong, R., & Peng, Y. (2020). The potential of
lonidamine in combination with chemotherapy and physical therapy in cancer
treatment. Cancers, 12(11), 3332.
Jacquet, P., & Stéphanou, A. (2022). Searching for the metabolic signature of cancer: A review
from Warburg’s time to now. Biomolecules, 12(10), 1412.
Jaworska, M., Szczud?o, J., Pietrzyk, A., Shah, J., Trojan, S. E., Ostrowska, B., & Kocemba-
Pilarczyk, K. A. (2023). The Warburg effect: a score for many instruments in the
concert of cancer and cancer niche cells. Pharmacological Reports, 75(4), 876-890.
Keerthana, C. K., Rayginia, T. P., Shifana, S. C., Anto, N. P., Kalimuthu, K., Isakov, N., &
Anto, R. J. (2023). The role of AMPK in cancer metabolism and its impact on the
immunomodulation of the tumor microenvironment. Frontiers in Immunology, 14,
Kocianova, E., Piatrikova, V., & Golias, T. (2022). Revisiting the Warburg effect with focus
on lactate. Cancers, 14(24), 6028.
Koltai, T. (2022). The complex relationship between multiple drug resistance and the tumor
pH gradient: a review. Cancer Drug Resistance, 5(2), 277.
Korsakova, L., Krasko, J. A., & Stankevicius, E. (2021). Metabolic-targeted combination
therapy with dichloroacetate and metformin suppresses glioblastoma cell line growth
in vitro and in vivo. in vivo, 35(1), 341-348.
Liu, G. Y., & Sabatini, D. M. (2020). mTOR at the nexus of nutrition, growth, ageing and
disease. Nature reviews Molecular cell biology, 21(4), 183-203.
Martí i Líndez, A.-A., & Reith, W. (2021). Arginine-dependent immune responses. Cellular
and molecular life sciences, 78(13), 5303-5324.
Martínez-Reyes, I., & Chandel, N. S. (2021). Cancer metabolism: looking forward. Nature
Reviews Cancer, 21(10), 669-680.
Mirabile, A., Rivoltini, L., Daveri, E., Vernieri, C., Mele, R., Porcu, L., . . . Cascinu, S. (2020).
Metabolism and Immune Modulation in patients with solid tumors: systematic review
of preclinical and clinical evidence. Cancers, 12(5), 1153.
Moindjie, H., Rodrigues-Ferreira, S., & Nahmias, C. (2021). Mitochondrial metabolism in
carcinogenesis and cancer therapy. Cancers, 13(13), 3311.
Neophytou, C. M., Panagi, M., Stylianopoulos, T., & Papageorgis, P. (2021). The role of tumor
microenvironment in cancer metastasis: Molecular mechanisms and therapeutic
opportunities. Cancers, 13(9), 2053.
Pan, Y., Liu, L., Mou, X., & Cai, Y. (2023). Nanomedicine strategies in conquering and
utilizing the cancer hypoxia environment. ACS nano, 17(21), 20875-20924.
Robles-Flores, M., Moreno-Londoño, A. P., & Castañeda-Patlán, M. C. (2021). Signaling
pathways involved in nutrient sensing control in cancer stem cells: an overview.
Frontiers in Endocrinology, 12, 627745.
Safrhansova, L., Hlozkova, K., & Starkova, J. (2022). Targeting amino acid metabolism in
cancer. International review of cell and molecular biology, 373, 37-79.
Selvakumar, S. C., Preethi, K. A., Ross, K., Tusubira, D., Khan, M. W. A., Mani, P., . . . Sekar,
D. (2022). CRISPR/Cas9 and next generation sequencing in the personalized treatment
of Cancer. Molecular cancer, 21(1), 83.
Sun, N.-Y., & Yang, M.-H. (2020). Metabolic reprogramming and epithelial-mesenchymal
plasticity: opportunities and challenges for cancer therapy. Frontiers in Oncology, 10,
Tanabe, A., & Sahara, H. (2020). The metabolic heterogeneity and flexibility of cancer stem
cells. Cancers, 12(10), 2780.
Tsilingiris, D., Tzeravini, E., Koliaki, C., Dalamaga, M., & Kokkinos, A. (2021). The role of
mitochondrial adaptation and metabolic flexibility in the pathophysiology of obesity
and insulin resistance: an updated overview. Current Obesity Reports, 10, 191-213.
Vaupel, P., & Multhoff, G. (2021). Revisiting the Warburg effect: historical dogma versus
current understanding. The Journal of physiology, 599(6), 1745-1757.
Wang, B., Zhao, Q., Zhang, Y., Liu, Z., Zheng, Z., Liu, S., . . . Jiang, X. (2021). Targeting
hypoxia in the tumor microenvironment: a potential strategy to improve cancer
immunotherapy. Journal of Experimental & Clinical Cancer Research, 40, 1-16.
Wang, R. C., & Wang, Z. (2023). Precision medicine: disease subtyping and tailored treatment.
Cancers, 15(15), 3837.
Zheng, X., Fan, H., Liu, Y., Wei, Z., Li, X., Wang, A., . . . Lu, Y. (2022). Hypoxia boosts
aerobic glycolysis in carcinoma: a complex process for tumour development. Current
Molecular Pharmacology, 15(3), 487-501.
Zhuo, C., Zhang, J., Lee, J.-H., Jiao, J., Cheng, D., Liu, L., . . . Li, M. (2021). Spatiotemporal
control of CRISPR/Cas9 gene editing. Signal transduction and targeted therapy, 6(1),
Zou, Z., Tao, T., Li, H., & Zhu, X. (2020). mTOR signaling pathway and mTOR inhibitors in
cancer: progress and challenges. Cell & bioscience, 10(1), 31.
