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Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia
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Abstract
Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy. We show that the murine tumor lines B16 and MC38 differed in their ability to consume oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade. Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in tumor cells in vitro and in vivo, resulting in reduced intratumoral hypoxia. Although metformin monotherapy had little therapeutic benefit in highly aggressive tumors, combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumor clearance. Our data suggest tumor hypoxia acts as a barrier to immunotherapy and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to immunotherapy into those that receive clinical benefit. Cancer Immunol Res; 5(1); 9–16. ©2016 AACR.
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“Current studies have focused on the role of hypoxia-induced metabolic reprogramming in causing T cell dysfunction and exhaustion16,19,52–55.”
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Citations
Cites
Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy
Topalian, S. L., Drake, C. G., & Pardoll, D. M. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.03.001 · Cited by 4,229 · cited 7×
“org Cancer Immunol Res; 5(1) January 2017 11”
BackgroundInfluentialGenomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma
Hugo, W., Zaretsky, J. M., Sun, L., Song, C., Moreno, B. H., Hu-Lieskovan, S., Berent-Maoz, B., Pang, J., Chmielowski, B., Cherry, G., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.065 · Cited by 3,448
Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression
Chang, C.-H., Qiu, J., O’Sullivan, D., Buck, M. D., Noguchi, T., Curtis, J. D., Chen, Q., Gindin, M., Gubin, M. M., van der Windt, G. J. W., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.016 · Cited by 3,331 · cited 2×
“can be metabolically plastic, and are primed to utilize glucose in oxygen-poor conditions, glucose, too, can be limiting in the tumor microenvironment (15,16).”
BackgroundMetformin and reduced risk of cancer in diabetic patients
Evans, J. M. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., & Morris, A. D. (2005) · BMJ · doi:10.1136/bmj.38415.708634.f7 · Cited by 2,388 · cited 1×
“It is established that patients taking metformin for type II diabetes have a decreased risk of cancer (17, 18) and that much of the antitumor metformin effect can be attributed to T cells (19).”
BackgroundPosttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O’Sullivan, D., Huang, S. C.-C., van der Windt, G. J. W., Blagih, J., Qiu, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.016 · Cited by 2,204
Woo, S.-R., Turnis, M. E., Goldberg, M. V., Bankoti, J., Selby, M., Nirschl, C. J., Bettini, M. L., Gravano, D. M., Vogel, P., Liu, C. L., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-1620 · Cited by 1,647
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses
Ho, P.-C., Bihuniak, J. D., Macintyre, A. N., Staron, M., Liu, X., Amezquita, R., Tsui, Y.-C., Cui, G., Micevic, G., Perales, J. C., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.012 · Cited by 1,462 · cited 2×
“However, in the tumor microenvironment, as glucose is limiting, only cells able to effectively compete for glucose would experience an enhanced response (15, 16).”
BackgroundScharping, N. E., Menk, A. V., Moreci, R. S., Whetstone, R. D., Dadey, R. E., Watkins, S. C., Ferris, R. L., & Delgoffe, G. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.009 · Cited by 848
Self-citationAerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism
Peng, M., Yin, N., Chhangawala, S., Xu, K., Leslie, C. S., & Li, M. O. (2016) · Science · doi:10.1126/science.aaf6284 · Cited by 787 · cited 1×
“to effector function epigenetically and post-transcriptionally (26-28).”
Scharping, N. E., Menk, A. V., Moreci, R. S., Whetstone, R. D., Dadey, R., Watkins, S. C., Ferris, R. L., & Delgoffe, G. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.08.009 · Cited by 708 · cited 1×
“We have previously shown that T cells in the tumor microenvironment are at a metabolic disadvantage and repress oxidative metabolism (13).”
BackgroundSelf-citation
Cited by
Sorted by citations
Items 201–300 of 522
Ramos-Peñafiel, C. O., Olarte-Carrillo, I., Maldonado, R. C., Rozen‐Fuller, E., Kassack-Ipiña, J. J., Meléndez, G., Collazo-Jaloma, J., & Martínez‐Tovar, A. (2018) · Journal of Translational Medicine · doi:10.1186/s12967-018-1620-6 · Cited by 40
Miyahira, A. K., Sharp, A., Ellis, L., Jones, J. C., Kaochar, S., Larman, H. B., Quigley, D. A., Ye, H., Simons, J. W., Pienta, K. J., et al. (2019) · The Prostate · doi:10.1002/pros.23934 · Cited by 40
Sung, J., & Cheong, J. (2022) · Cells · doi:10.3390/cells11050768 · Cited by 40
“Metformin also improves the response to PD-1 blockade in tumor models that are resistant to checkpoint blockade [63].”
BackgroundLiu, X., Zhao, Y., Wu, X., Liu, Z., & Liu, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.931104 · Cited by 41
“A combination of metformin with PD-1 antibody improves T-cell function and tumor clearance in mice with melanoma (84).”
BackgroundIntegrating T cell metabolism in cancer immunotherapy
Dugnani, E., Pasquale, V., Bordignon, C., Canu, A., Piemonti, L., & Monti, P. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.09.039 · Cited by 38
Metformin Effects on FOXP3+ and CD8+ T Cell Infiltrates of Head and Neck Squamous Cell Carcinoma
Amin, D. R., Richa, T., Mollaee, M., Zhan, T., Tassone, P. T., Johnson, J. M., Luginbuhl, A., Cognetti, D. M., Martinez‐Outschoorn, U., Stapp, R., et al. (2019) · The Laryngoscope · doi:10.1002/lary.28336 · Cited by 37
Metabolic Implications of Immune Checkpoint Proteins in Cancer
Stirling, E. R., Bronson, S. M., Mackert, J. D., Cook, K. L., Triozzi, P. L., & Soto‐Pantoja, D. R. (2022) · Cells · doi:10.3390/cells11010179 · Cited by 39
“Presumably, this reduction in hypoxia would shift nutrient availability in the tumor microenvironment facilitating metabolic reprogramming of T cells and response to immune checkpoint blockade therapies [151].”
BackgroundTajaldini, M., Poorkhani, A., Amiriani, T., Amiriani, A., Javid, H., Aref, P., Ahmadi, F., Sadani, S., & Khori, V. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.175991 · Cited by 38
Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer
Robles-Oteíza, C., Hastings, K., Choi, J., Sirois, I., Ravi, A., Expósito, F., de Miguel, F. J., Knight, J., López‐Giráldez, F., Choi, H., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20231106 · Cited by 39
“…outcomes in patients who received metformin with ICIs (Kim et al., 2021; Wu et al., 2021), together with compelling results in murine models (Scharping et al., 2017) provide a rationale for additional clinical studies of metformin combined with ICIs (e.g., NCT04114136, NCT03994744,…”
Ferroptosis in Cancer and Inflammatory Diseases: Mechanisms and Therapeutic Implications
Shen, G., Liu, J., Wang, Y., Deng, Z., & Deng, F. (2025) · MedComm · doi:10.1002/mco2.70349 · Cited by 47
Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy
Hope, H. C., & Salmond, R. J. (2019) · European Journal of Immunology · doi:10.1002/eji.201848058 · Cited by 38
Mostafavi, S., Zalpoor, H., & Hassan, Z. M. (2022) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-022-00356-2 · Cited by 41
“By the same token, the more oxidative metabolism that occurs in the tumor, the greater the exhaustion in T cells [144].”
BackgroundZhang, M., Chen, X., & Radacsi, N. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.11.047 · Cited by 36
Translation of cancer immunotherapy from the bench to the bedside
Guo, Q., Huang, F., Gonçalves, C., Rincon, S. V. D., & Miller, W. H. (2019) · Advances in cancer research · doi:10.1016/bs.acr.2019.03.001 · Cited by 35
Interaction between Immunotherapy and Antiangiogenic Therapy for Cancer
Furukawa, K., Nagano, T., TACHIHARA, M. Y., Yamamoto, M., & Nishimura, Y. (2020) · Molecules · doi:10.3390/molecules25173900 · Cited by 36
Chen, Y., Yu, Z., Lv, M., Cai, Z., Zou, Y., Lan, P., Wu, X., & Gao, F. (2021) · Molecular Medicine · doi:10.1186/s10020-021-00402-3 · Cited by 35
SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery
Hu‐Lieskovan, S., Bhaumik, S., Dhodapkar, K. M., Grivel, J., Gupta, S. V., Hanks, B. A., Janetzki, S., Kleen, T. O., Koguchi, Y., Lund, A. W., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000705 · Cited by 35
Trucco, M. M., Barredo, J. C., Goldberg, J., Leclerc, G. M., Hale, G. A., Gill, J. B., Setty, B. A., Smith, T., Lush, R. M., Lee, J. K., et al. (2018) · Pediatric Blood & Cancer · doi:10.1002/pbc.27224 · Cited by 34
Jacobi, O., Landman, Y., Reinhorn, D. J., Icht, O., Sternschuss, M., Rotem, O., Finkel, I., Allen, A. M., Dudnik, E., Goldstein, D. A., et al. (2021) · Oncology · doi:10.1159/000516671 · Cited by 34
Morehead, L. C., Garg, S., Wallis, K., Simões, C., Siegel, E. R., Tackett, A. J., & Miousse, I. R. (2023) · Cancers · doi:10.3390/cancers15184467 · Cited by 32
“The increase in MHC-I expression translated into an increased display of antigens on the cell surface, as a tt ested by the increase in the presence of the SIINFEKL peptide conjugated to MHC-I at the surface of murine B16F10 OVA cells.”
BackgroundWu, C., Xu, T.-H., Zhang, H.-Y., Hu, Y., Jiao, J., Qiu, K., Gu, J., Li, W.-Y., & Sun, L. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217913 · Cited by 32
Role of dendritic cell metabolic reprogramming in tumor immune evasion
Plebanek, M. P., Sturdivant, M. S., DeVito, N. C., & Hanks, B. A. (2020) · International Immunology · doi:10.1093/intimm/dxaa036 · Cited by 31
Zhang, L., Jin, Q., Chai, D., Kuang, T., Li, C., Guan, Y., Liu, L., Wang, W., & Deng, W. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.937874 · Cited by 31
“While most drugs have side effects and are sometimes harmful to the patient, probiotics have few side effects (Forslund et al., 2015; Kim et al., 2017; Scharping et al., 2017; Wu et al., 2017; Cha et al., 2018).”
BackgroundNkune, N. W., & Abrahamse, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032656 · Cited by 34
Kubo, T., Ninomiya, T., Hotta, K., Kozuki, T., Toyooka, S., Okada, H., Fujiwara, T., Udono, H., & Kiura, K. (2018) · Clinical Lung Cancer · doi:10.1016/j.cllc.2018.07.010 · Cited by 32
“Although metformin monotherapy has shown little therapeutic benefit against highly aggressive tumors, a combination of metformin and PD-1 blockade has been reported to improve intratumoral T-cell function and tumor clearance.(13)”
Immunosurveillance encounters cancer metabolism
Chuang, Y., Tzeng, S., Ho, P., & Tsai, C. (2024) · EMBO Reports · doi:10.1038/s44319-023-00038-w · Cited by 33
“In a B16 melanoma mouse model, metformin promoted ef fi cacy of PD-1 blockade by reinvigorating T cells (Scharping et al, 2017).”
BackgroundMetabolic rewiring in melanoma drug-resistant cells
Bristot, I. J., Dias, C. K., Chapola, H., Parsons, R. B., & Klamt, F. (2020) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2020.102995 · Cited by 34
T Cell Metabolism in Cancer Immunotherapy
Aksoylar, H., Tijaro-Ovalle, N. M., Boussiotis, V. A., & Patsoukis, N. (2020) · Immunometabolism · doi:10.20900/immunometab20200020 · Cited by 31
“Strikingly, increased OXPHOS favored differentiation to Th17 phenotype as TCR-dependent induction of the Th17 transcription factor basic leucine zipper transcription factor TF-like (BATF) was partially regulated by mTORC1 activation, which required ATP-linked mitochondrial OXPHOS [57].”
BackgroundInfluentialPD-1 immunobiology in glomerulonephritis and renal cell carcinoma
Curran, C. S., & Kopp, J. B. (2021) · BMC Nephrology · doi:10.1186/s12882-021-02257-6 · Cited by 30
“In a murine melanoma model, a combination of metformin and PD-1 blockade results in improved intratumoral T-cell function and tumor clearance [148].”
BackgroundRepas, J., Zupin, M., Vodlan, M., Veranič, P., Gole, B., Potočnik, U., & Pavlin, M. (2022) · Cancers · doi:10.3390/cancers14051343 · Cited by 32
“The effect of metformin and 2DG are also importantly impacted by nutrient availability [41,45,46].”
BackgroundA clinically acceptable strategy for sensitizing anti-PD-1 treatment by hypoxia relief
Jiang, M., Qin, B., Luo, L., Li, X., Shi, Y., Zhang, J., Luo, Z., Zhu, C., Guan, G., Du, Y., et al. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.06.001 · Cited by 30
Hypoxia, a Targetable Culprit to Counter Pancreatic Cancer Resistance to Therapy
Khouzam, R. A., Lehn, J., Mayr, H., Clavien, P., Wallace, M. B., Ducreux, M. P., Limani, P., & Chouaïb, S. (2023) · Cancers · doi:10.3390/cancers15041235 · Cited by 33
Hypoxic tumor microenvironment: Destroyer of natural killer cell function
Zhang, Y., Guo, F., & Wang, Y. (2024) · Chinese Journal of Cancer Research · doi:10.21147/j.issn.1000-9604.2024.02.04 · Cited by 32
Nyambuya, T. M., Dludla, P. V., Mxinwa, V., Mokgalaboni, K., Ngcobo, S. R., Tiano, L., & Nkambule, B. B. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117854 · Cited by 30
Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)—T Cells
Rad, S. M. A. H., Halpin, J. C., Mollaei, M., Smith‐Bell, S. W., Hirankarn, N., & McLellan, A. D. (2021) · Cancers · doi:10.3390/cancers13061229 · Cited by 31
Tryptophan and Its Metabolites in Lung Cancer: Basic Functions and Clinical Significance
Li, C., & Zhao, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.707277 · Cited by 31
“Furthermore, LC patients with lower plasma 3-HAA, the precursor of QA, benefit more from ICI treatment, suggesting that plasma 3-HAA levels may be a biomarker for predicting the response of LC patients to ICIs (23).”
BackgroundInfluentialChow, E., Yang, A., Chung, C. H. L., & Chan, J. C. N. (2022) · Pharmaceuticals · doi:10.3390/ph15040442 · Cited by 30
“By reducing oxygen and glucose consumption by tumor cells and increasing the intratumor oxygen levels, metformin sensitized patients’ responses to programmed death-ligand 1 (PD-L1) chemotherapy [118].”
BackgroundXu, X., Chen, Z., Bartman, C., Xing, X., Olszewski, K. L., & Rabinowitz, J. D. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.04.007 · Cited by 32
Fischer, G. M., Guerrieri, R. A., Hu, Q., Joon, A. Y., Kumar, S., Haydu, L. E., McQuade, J. L., Gopal, Y. N. V., Knighton, B. G., Deng, W., et al. (2021) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdaa177 · Cited by 29
Immuno-Metabolism: The Role of Cancer Niche in Immune Checkpoint Inhibitor Resistance
Weng, C.-Y., Kao, C.-X., Chang, T., & Huang, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031258 · Cited by 29
“The capacity of CD8+ T cells to secrete effector cytokines is enhanced by administration of metformin with anti-PD-1 compared with either metformin or anti-PD-1 alone [198].”
BackgroundAdvances in metformin‑based metabolic therapy for non‑small cell lung cancer (Review)
Chen, N., Zhou, Y.-S., Wang, L.-C., & Huang, J. (2022) · Oncology Reports · doi:10.3892/or.2022.8266 · Cited by 29
Dong, K., Gu, D., Shi, J., Bao, Y., Fu, Z., Fang, Y., Qu, L., Zhu, W., Jiang, A., & Wang, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.874792 · Cited by 29
Role of Hypoxia in the Interferon Response
Arnaiz, E., & Harris, A. L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.821816 · Cited by 28
Lin, R., Yan, J., Gong, B., Tong, F., Song, Y., Xia, X., Hu, H., Wang, Y., Zhou, Y., Gong, T., et al. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202405051 · Cited by 28
Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions
Cote, A. L., Munger, C. J., & Ringel, A. E. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115234 · Cited by 29
Ascierto, P. A., Bifulco, C. B., Buonaguro, L., Emens, L. A., Ferris, R. L., Fox, B. A., Delgoffe, G. M., Galon, J., Gridelli, C., Merlano, M. C., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0798-3 · Cited by 28
“Metformin, a widely prescribed type 2 diabetes treatment, inhibited oxygen consumption in tumor cells in murine tumor lines resulting in reduced intratumoral hypoxia [13].”
BackgroundSelf-citationImmunometabolic Alterations by HPV Infection: New Dimensions to Head and Neck Cancer Disparity
Chaudhary, S., Ganguly, K., Muniyan, S., Pothuraju, R., Sayed, Z., Jones, D. T., Batra, S. K., & Macha, M. A. (2018) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djy207 · Cited by 31
Strategies to Interfere with Tumor Metabolism through the Interplay of Innate and Adaptive Immunity
Mora, J., Mertens, C., Meier, J. K., Fuhrmann, D. C., Brüne, B., & Jung, M. (2019) · Cells · doi:10.3390/cells8050445 · Cited by 27
Tumor hypermetabolism confers resistance to immunotherapy
Liu, A. J., & Curran, M. A. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.01.009 · Cited by 29
Lobb, R. J., Visan, K. S., Wu, L., Norris, E. L., Hastie, M. L., Everitt, S., Yang, I. A., Bowman, R., Siva, S., Larsen, J. E., et al. (2023) · Communications Biology · doi:10.1038/s42003-022-04350-4 · Cited by 28
“Within the tumour microenvironment, hypoxia alters numerous physiological functions, including angiogenesis, metabolism, immune cell function and EMT, thereby promoting metastasis 31 .”
Chae, Y. K., Oh, M. S., & Giles, F. J. (2017) · The Oncologist · doi:10.1634/theoncologist.2017-0354 · Cited by 28
“Tumor hypoxia has also raised interest as a resistance factor, and signals activated by hypoxic environments were associated with worse clinical outcomes in mice treated with PD-1 blockade [91].”
BackgroundMetformin: (future) best friend of the radiation oncologist?
Chevalier, B., Pasquier, D., Lartigau, E. F., Chargari, C., Schernberg, A., Jannin, A., Mirabel, X., Vantyghem, M., & Escande, A. (2020) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2020.06.030 · Cited by 27
A new aspect of an old friend: the beneficial effect of metformin on anti-tumor immunity
Kim, K., Yang, W., Jung, Y., & Cha, J. (2020) · BMB Reports · doi:10.5483/bmbrep.2020.53.10.149 · Cited by 29
“Furthermore, metformin-treated breast cancer patients’ data and animal work strongly support that a combination of metformin with a non-PD-1/PD-L1 targeting ICB can be effective in treating patients with PD-L1-expressing tumors.”
BackgroundInfluentialTargeting oxidative phosphorylation as an approach for the treatment of ovarian cancer
Wu, Y., Zhang, X., Wang, Z., Zheng, W., Cao, H., & Shen, W. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.971479 · Cited by 27
“Metformin alone brings limited therapeutic benefit in highly aggressive tumors, whereas combination of metformin with PD-1 blockade improves anti-tumor effect of T cells (39).”
BackgroundTian, J., Luo, J., Zeng, X., Ke, C., Wang, Y., Liu, Z., Li, L., Zhang, Y., Hu, Z., & Yang, C. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-008226 · Cited by 28
Self-citationCai, W., Sun, T., Qiu, C., Sheng, H., Chen, R., Xie, C., Kou, L., & Yao, Q. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02925-3 · Cited by 26
“Metformin (Met), a medication commonly used for treating diabetes, has shown remarkable potential in tumor immunotherapy [76–78].”
BackgroundLin, A. G., Sahun, M., Biscop, E., Verswyvel, H., Waele, J. D., Backer, J. D., Theys, C., Cuypers, B., Laukens, K., Berghe, W. V., et al. (2022) · Drug Resistance Updates · doi:10.1016/j.drup.2022.100914 · Cited by 27
Quan, Y., He, J., Zou, Q., Zhang, L., Sun, Q., Huang, H., Li, W., Xie, K., & Wei, F. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007080 · Cited by 26
Li, H., Zhang, L., Yang, F., Zhao, R., Li, X., & Li, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1218386 · Cited by 27
“Although preclinical studies have found that metformin can synergize with programmed death-1 (PD-1) inhibitors (59), some retrospective studies have shown that metformin does not affect the ef fi cacy of ICIs.”
BackgroundPredicting tumour response to anti-PD-1 immunotherapy with computational modelling
Valentinuzzi, D., Simončič, U., Uršič, K., Vrankar, M., Turk, M., & Jeraj, R. (2018) · Physics in Medicine and Biology · doi:10.1088/1361-6560/aaf96c · Cited by 26
Mata, M., & Gottschalk, S. M. (2019) · Drugs · doi:10.1007/s40265-019-01071-7 · Cited by 25
Gut microbiome: A possible common therapeutic target for treatment of atherosclerosis and cancer
Wu, W., Ivanova, E. A., & Orekhov, A. N. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.06.017 · Cited by 26
Immunometabolism: A ‘Hot’ Switch for ‘Cold’ Pediatric Solid Tumors
Xiao, L., Yeung, H., Haber, M., Norris, M. D., & Somers, K. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.05.002 · Cited by 24
Improving Cancer Immunotherapy: Exploring and Targeting Metabolism in Hypoxia Microenvironment
Wei, J., Hu, M., & Du, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.845923 · Cited by 28
“Inhibiting OXPHOS by Ndufs4 knockdown in tumor cells or metformin treatment has reduced hypoxic environments and enhanced PD-1 blockade efficacy (34, 66).”
BackgroundRole of Bladder Cancer Metabolic Reprogramming in the Effectiveness of Immunotherapy
Scholtes, M., de Jong, F. C., Zuiverloon, T. C. M., & Theodorescu, D. (2021) · Cancers · doi:10.3390/cancers13020288 · Cited by 24
“Preclinical models have demonstrated that disrupting lactate transport with diclofenacmediated MCT-inhibition, neutralizing intratumoral pH with oral bicarbonate treatment, or counteracting intratumoral hypoxia with metformin can synergize with ICT [68,76] In conclusion, disrupting UC metabolism may be a new approach…”
BackgroundInfluentialLuo, X., Chen, X., Wang, L., Yang, B., & Cai, S. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.639016 · Cited by 24
“Moreover, remodeling the hypoxic tumor microenvironment and blocking the inhibitory signal of PD-L1 by metformin enhances cytotoxic T lymphocyte (CTL) activity against cancer cells, which increases the efficacy of immunotherapy drugs (Scharping et al., 2017; Cha et al., 2018).”
BackgroundSynergistic effect of antimetabolic and chemotherapy drugs in triple-negative breast cancer
López‐Camacho, E., Trilla‐Fuertes, L., Gámez‐Pozo, A., Dapía, I., López‐Vacas, R., Zapater‐Moros, A., Lumbreras-Herrera, M. I., Arias, P., Zamora, P. M., Vara, J. Á. F., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112844 · Cited by 31
HIF-1 regulates pathogenic cytotoxic T cells in lupus skin disease
Little, A. J., Chen, P.-M., Vesely, M. D., Khan, R. N., Fiedler, J., Garritano, J., Maisha, F. I., McNiff, J. M., & Craft, J. E. (2023) · JCI Insight · doi:10.1172/jci.insight.166076 · Cited by 27
Rodríguez‐Berriguete, G., Puliyadi, R., Machado, N., Barberis, A., Prevo, R., McLaughlin, M., Buffa, F. M., Harrington, K. J., & Higgins, G. S. (2024) · Cell Death and Disease · doi:10.1038/s41419-023-06405-8 · Cited by 25
“Scharping et al. [29] reported a therapeutic bene fi t when combining aPD-1 and metformin in the MC38 model, which somehow contrasts with the lack of bene fi t reported in the present study when adding atovaquone to aPD-L1 in this model.”
ResultOrlandella, R. M., Turbitt, W. J., Gibson, J. T., Boi, S. K., Li, P., Smith, D. L., & Norian, L. A. (2020) · Cancers · doi:10.3390/cancers12102872 · Cited by 24
Wu, B., Sun, X., Yuan, B., Ge, F., Gupta, H. B., Chiang, H.-C., Li, J., Hu, Y., Curiel, T. J., & Li, R. (2020) · International Journal of Biological Sciences · doi:10.7150/ijbs.42966 · Cited by 23
“Because several antidiabetic drugs have potential antitumor effects; either by themselves or in combination with immunotherapy in preclinical melanoma models [36,37], they could confound interpretation of obesity association with immunotherapy outcomes.”
BackgroundKalyanaraman, B. (2022) · The FASEB Journal · doi:10.1096/fj.202101862r · Cited by 23
Mutually reinforced cancer treatment based on phototherapy combined with ferroptosis
Chen, G., Gan, L., Tian, L.-Y., Huang, B.-X., Xiao, Q., Zhang, Y., Xiao, M., Zheng, B.-D., & Ye, J. (2024) · Chemical Engineering Journal · doi:10.1016/j.cej.2024.152397 · Cited by 23
Recent research progress and clinical status of immunotherapy for colorectal cancer
Huo, Z., Liu, G., & Li, J. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.06.089 · Cited by 27
Rewiring cancer metabolism: oncogenic signaling pathways and targeted therapeutics
Lyu, S., Gildor, N., Zhang, Q. H., & Liao, C. (2025) · Science China Life Sciences · doi:10.1007/s11427-025-2979-3 · Cited by 27
“For example, synergist effects between PD-1 blockade and high-dose vitamin C have been observed in mouse tumor models (Magrì et al., 2020), and combining metformin with PD-1 blockade has enhanced T cell activation and tumor control (Scharping et al., 2017).”
Chao, R., Nishida, M., Yamashita, N., Tokumasu, M., Zhao, W., Kudo, I., & Udono, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.864225 · Cited by 23
“In another study, Met was shown to enhance the effect of the cancer immunotherapy of PD-1 blockade in the MC38 (colon carcinoma) model; the effect was attributed to the improvement in tumor hypoxia following the OxPhos inhibition in tumor cells by Met (12).”
BackgroundMetabolism heterogeneity in melanoma fuels deactivation of immunotherapy: Predict before protect
Zhang, X., Tai, Z., Miao, F., Huang, H., Zhu, Q., Bao, L., & Chen, Z. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1046102 · Cited by 22
Savva, C., Copson, E., Johnson, P., Cutress, R., & Beers, S. A. (2023) · Cancers · doi:10.3390/cancers15092440 · Cited by 21
Augustin, R. C., Huang, Z., Ding, F., Zhai, S., McArdle, J., Santisi, A., Davis, M., Sander, C., Davar, D., Kirkwood, J. M., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1075823 · Cited by 24
“It is now well understood that immunosuppressive and metabolically hostile TME, including decreased pH, altered amino acid metabolism, mitochondrial dysfunction, and hypoxia have substantial effects on the phenotype and function of TIL (8).”
BackgroundMethodInfluentialSelf-citationLuo, H., Wang, W., Mai, J., Yin, R., Cai, X., & Li, Q. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1267918 · Cited by 22
Liao, L., Xu, H., Zhao, Y., & Zheng, X. (2023) · Frontiers of Medicine · doi:10.1007/s11684-023-1025-7 · Cited by 22
Ioning out glioblastoma: ferroptosis mechanisms and therapeutic frontiers
Sun, H., Zhang, J., Qi, H., Jiang, D., Hu, C., Mao, C., Liu, W., Qi, H., & Zong, J. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02711-6 · Cited by 23
“Due to the rapid proliferation of GBM, the TME is suppressed by factors such as acidity and hypoxia, rendering immunotherapy ineffective [95, 96].”
An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin
Tardón, M. C., Marinari, E., Migliorini, D., Bes, V., Tankov, S., Charrier, E., McKee, T., Dutoit, V., Dietrich, P., Cosset, E. C., et al. (2020) · Biology · doi:10.3390/biology9090264 · Cited by 21
Anti-hypoxia nanosized drug delivery systems improving cancer therapy
Yan, W., Lang, T., Zhu, R., Zhu, X. G., Yu, H., Wu, T., Yin, Q., & Li, Y. (2022) · Nano Today · doi:10.1016/j.nantod.2022.101376 · Cited by 21
Nutrient allocation fuels T cell-mediated immunity
Longo, J., Watson, M. J., Williams, K. S., Sheldon, R. D., & Jones, R. G. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.09.008 · Cited by 19
Dhupar, R., Okusanya, O. T., Eisenberg, S. H., Monaco, S. E., Ruffin, A. T., Liu, D., Luketich, J. D., Kammula, U. S., Bruno, T. C., Lotze, M. T., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176178 · Cited by 20
“Studies of the microenvironment within solid tumors have implicated hypoxia [1,2], nutrient availability [3–5], suppressive cytokines [6,7], other molecules (e.”
BackgroundHamy, A., Derosa, L., Valdelièvre, C., Yonekura, S., Opolon, P., Priour, M., Guerin, J., Pierga, J., Asselain, B. J. R., Croze, D. D., et al. (2019) · OncoImmunology · doi:10.1080/2162402x.2019.1677427 · Cited by 22
Impact of metformin on immunological markers: Implication in its anti-tumor mechanism
Chen, G. G., Woo, P. Y., Ng, S. C. P., Wong, G. K. C., Chan, D. T.-M., van Hasselt, C. A., Tong, M. C. F., & Poon, W. S. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107585 · Cited by 20
Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers
King, R., Hayes, C., Donohoe, C. L., Dunne, M. R., Davern, M., & Donlon, N. E. (2021) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v13.i5.312 · Cited by 20
Yang, J., Kim, S. H., Jung, E. H., Kim, S., Suh, K. J., Lee, J. Y., Kim, J., Kim, J. W., Lee, J., Kim, Y. J., et al. (2022) · Thoracic Cancer · doi:10.1111/1759-7714.14711 · Cited by 20
“Notably, metformin also remodels the TME by inhibiting the oxygen intake of tumors and blocking the accumulation of myeloid-derived suppressor cells.(24,25) T A B L E 5 Immune-related adverse events”
BackgroundNew Developments in T Cell Immunometabolism and Implications for Cancer Immunotherapy
Oberholtzer, N. P., Quinn, K. M., Chakraborty, P., & Mehrotra, S. (2022) · Cells · doi:10.3390/cells11040708 · Cited by 19
Hahn, A. W., Venkatesh, N., Msaouel, P., & McQuade, J. L. (2023) · Cells · doi:10.3390/cells12212551 · Cited by 21
Intrinsic and Extrinsic Determinants of T Cell Metabolism in Health and Disease
Munford, H., & Dimeloe, S. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00118 · Cited by 19
“…models of melanoma identified that anti-PD-1 treatment was most effective when tumor oxidative metabolism was also genetically or pharmacologically inhibited—resulting in higher intra-tumoral oxygen levels and improved T cell anti-tumor function (Scharping et al., 2017; Najjar et al., 2019).”
BackgroundMetabolic Regulation of CD8 + T Cells: From Mechanism to Therapy
Zheng, Y. Y., Wang, X., & Huang, M. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0040 · Cited by 19
“Another study compared the functions of CD8 + T cells infiltrated in tumors with different lactate levels and revealed that pathophysiological concentrations of lactate reduced the generation of IFN-c and granzyme-B by inducing intracellular acidification (14).”
InfluentialMetformin: A Promising Antidiabetic Medication for Cancer Treatment
Mu, W., Jiang, Y., Liang, G., Feng, Y., & Qu, F. (2022) · Current Drug Targets · doi:10.2174/1389450124666221104094918 · Cited by 18
Metabolic Challenges in Anticancer CD8 T Cell Functions
Amitrano, A. M., & Kim, M. (2023) · Immune Network · doi:10.4110/in.2023.23.e9 · Cited by 20
“Recent studies have shown that the hypoxic TME, in addition to chronic antigen stimulation, inhibits mitochondrial ATP production as well as T-cell proliferation and effector functions, thus reducing therapy efficacy (7,36,92,93).”
BackgroundDeciphering the tumour immune microenvironment cell by cell
Nabhan, M., Egan, D., Kreileder, M., Zhernovkov, V., Timosenko, E., Slidel, T. W. F., Dovedi, S. J., Glennon, K., Brennan, D. J., & Kölch, W. (2023) · Immuno-Oncology Technology · doi:10.1016/j.iotech.2023.100383 · Cited by 17
“100383 CD137, can re-programme the TME, promote tumour regression and sensitize tumours to ICIs in vivo.(63,66,71,72) Importantly, it is not just infiltrating immune cells but also tumour stromal cells that can shape the TME and outcomes of cancer therapy.”
BackgroundThe development and benefits of metformin in various diseases
Dong, Y., Qi, Y., Jiang, H., Tian, M., Zhang, Y., Peng, C. S., Li, W.-C., Zhang, Y., Zhou, Y., Zang, Y., et al. (2023) · Frontiers of Medicine · doi:10.1007/s11684-023-0998-6 · Cited by 21
Kemnade, J. O., Florez, M. A., Sabichi, A. L., Zhang, J., Jhaveri, P. M., Chen, G., Chen, A. C., Miller-Chism, C. N., Bulsara, S., Hilsenbeck, S. G., et al. (2023) · Oral Oncology · doi:10.1016/j.oraloncology.2023.106536 · Cited by 18
Jones, V., Dietze, E. C., Jovanović‐Talisman, T., McCune, J. S., & Seewaldt, V. L. (2020) · Frontiers in Public Health · doi:10.3389/fpubh.2020.509714 · Cited by 19
Metadata
- Authors
- Scharping, N. E., Menk, A. V., Whetstone, R. D., Zeng, X., & Delgoffe, G. M.
- Affiliations
- University of Pittsburgh (US)
- UPMC Hillman Cancer Center (US)
- Corresponding author
- Delgoffe, Greg M.
- Venue
- Cancer Immunology Research
- Published
- 2017-01-01
- Volume
- 5
- Issue
- 1
- Pages
- 9-16
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC5340074
- OpenAlex
- W2560185130
- Cited by
- 520
- References
- 30
- Citations by year
- 2026: 34 · 2025: 53 · 2024: 49 · 2023: 72 · 2022: 85 · 2021: 79 · 2020: 69 · 2019: 38 · 2018: 30 · 2017: 11
- FWCI
- 14.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- UPCI (P30CA047904)
- Sidney Kimmel Foundation for Cancer Research (SKF-015-039)
- University of Pittsburgh Cancer Institute Skin Cancer (P50CA121973-08)
- University of Pittsburgh Cancer Institute Head and Neck Cancer SPORE (P50 CA097190)
- Cancer-AACR Innovative Research (SU2C-AACR-IRG-04-16)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- anti-PD-1 therapy, metformin, tumor hypoxia, tumor microenvironment, cancer immunotherapy resistance, combination therapy, oxidative metabolism, T cell function, B16 melanoma, MC38 colon carcinoma, antitumor immunity
- MeSH terms
- Tumor Hypoxia, Antineoplastic Agents, Immunological, Animals, Cytotoxicity, Immunologic, Drug Synergism, Energy Metabolism, Melanoma, Experimental, Metformin, Oxygen Consumption, T-Lymphocytes, Cytokines, Lymphocytes, Tumor-Infiltrating, Mice, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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