Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice
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Immunotherapy has expanded treatment options for cancers with historically poor outcomes, yet a significant proportion of patients still fail to achieve durable clinical benefit. We defined the contribution of β-adrenergic receptor (βAR) signaling, a component of the stress response, on success of immunotherapy for melanoma since the use of antagonists (β-blockers) is associated with improved clinical outcomes in some cancers. We show that metastatic melanoma patients who received immunotherapy had improved overall survival if they also received pan β-blockers. This retrospective analysis is reinforced by results showing that βAR blockade enhances the control of murine melanoma growth by anti-(α)PD-1 checkpoint blockade. However, this effect was most significant when β-blocker was combined with dual αPD-1 + high dose interleukin-2 therapy and was reproduced by selective blockade of β2ARs. These results identify a novel strategy that can be quickly introduced to potentially increase the number of patients who benefit from immune-based therapies.
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Chronic activation of the sympathetic axis through βAR signaling suppresses cytotoxic T-cell function, whereas β-blockade restores effector activity and improves survival in patients receiving immunotherapy.
“Chronic activation of the sympathetic axis through βAR signaling suppresses cytotoxic T-cell function, whereas β-blockade restores effector activity and improves survival in patients receiving immunotherapy.117”
From Gut dysbiosis in oncology: a risk factor for immunoresistance (2026) · cites this paper as [117]
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The neural addiction of cancer
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“In melanoma, pan β-blocker use correlated with significantly better OS 111 , and a prospective study found a 78% overall response rate with pembrolizumab plus propranolol 128 .”
The cancer-immune dialogue in the context of stress
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“551 or propranolol), but not the blockade of β 1 -ARs (with meto-prolol) 154 , enhanced the efficacy of anti-PD1 therapy in mouse models of melanoma and breast cancer 154,155 .”
Neuro-immune interactions and immuno-oncology
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“A series of preclinical studies has demonstrated the protective mechanisms of propranolol, which include reducing invasion and angiogenesis (9,16) and improving anti-cancer immunity (26).”
BackgroundChronic stress in solid tumor development: from mechanisms to interventions
Yan, J., Chen, Y., Luo, M., Hu, X., Li, H., Liu, Q., & Zou, Z. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-023-00903-9 · Cited by 84 · see citing works
Exercise and adrenergic regulation of immunity
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Self-citationNeural control of immune cell trafficking
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β 3 ‐Adrenoceptor as a potential immuno‐suppressor agent in melanoma
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The systemic hallmarks of cancer
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“A group of researchers at Penn State University found that melanoma patients who received immunotherapy while taking pan β-blockers lived longer than patients who received immunotherapy alone or patinets that received immunotherapy and β1-selective blockers([249]).”
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“Similar results were observed in another melanoma-bearing mouse model treated with anti-PD1 with or without IL-2 in combination with propranolol 55 .”
ResultKennedy, O. J., Kiciński, M., Valpione, S., Gandini, S., Suciu, S., Blank, C. U., Long, G. V., Atkinson, V. G., Dalle, S., Haydon, A. M., et al. (2022) · European Journal of Cancer · doi:10.1016/j.ejca.2022.01.017 · Cited by 58 · see citing works
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The Use of Antihypertensive Drugs as Coadjuvant Therapy in Cancer
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Self-citationBodywide ecological interventions on cancer
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“Since the initiation of this trial, reported data continue to support the benefit of nonselective betablockade in other types of cancers.[31, 32] De Giorgi et al.”
BackgroundWang, L., Ge, J., Han, H., Jia, Y., & Qin, Y. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216986 · Cited by 48 · see citing works
Trial watch: beta-blockers in cancer therapy
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“This is consistent with the fact that the synergistic effect of PRO with PD-Li inhibition was previously shown in melanoma (Kokolus, 2018) and tested in patients with metastatic melanoma (Gandhi, 2021).”
BackgroundBeta‐blockers exert potent anti‐tumor effects in cutaneous and uveal melanoma
Bustamante, P., Miyamoto, D., Goyeneche, A. A., Graue, P. G. D. A., Jin, E., Tsering, T., Dias, A. B. T., Burnier, M. N., & Burnier, J. V. (2019) · Cancer Medicine · doi:10.1002/cam4.2594 · Cited by 42 · see citing works
Beta-Adrenergic Signaling in Tumor Immunology and Immunotherapy
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Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence
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“45–52 Other BBs, such as the beta1-selective metoprolol 41 and ne-bivolol, 53,54 as well as the non-selective labetalol 33 were also shown to have either anti-cancer effects per se , or enhance the anti-cancer effects of other drugs.”
BackgroundThe interplay among psychological distress, the immune system, and brain tumor patient outcomes
Otto‐Meyer, S., Lumibao, J. C., Kim, E., Ladomersky, E., Zhai, L., Lauing, K. L., Scholtens, D. M., Penedo, F. J., Amidei, C., Lukas, R. V., et al. (2019) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2019.01.009 · Cited by 39 · see citing works
“Additionally, recent studies found that the inhibition of b-adrenergic signaling with the pan-beta blocker propranolol enhances PD-1 checkpoint inhibitor efficacy in preclinical, syngeneic, mouse melanoma models [54,56].”
Circulating epinephrine is not required for chronic stress to enhance metastasis
Walker, A. K., Martelli, D., Ziegler, A. I., Lambert, G. W., Phillips, S. E., Hill, S. J., McAllen, R. M., & Sloan, E. K. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.09.012 · Cited by 38 · see citing works
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Cavalu, S. D., Saber, S., Amer, A. E., Hamad, R. S., Abdel‐Reheim, M. A., Elmorsy, E. A., & Abdelhamid, A. M. (2024) · The FASEB Journal · doi:10.1096/fj.202400725rr · Cited by 37 · see citing works
“87 In another retrospective study of 109 non-small cell lung cancer patients, progression-free survival was attenuated among patients treated with beta-blockers and immune checkpoint inhibitors relative to immune checkpoint inhibitors without beta blockers.”
InfluentialThe neuro-immune axis in cancer: from mechanisms to therapeutic opportunities
Zhang, C., Guo, X., Liu, P., Wang, Y., Zhang, J., Li, L., Wu, K., Xiao, J., Mei, Q., & Wang, Z. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-025-01748-5 · Cited by 42 · see citing works
“Another clinical study in patients with metastatic melanoma showed that concurrent treatment with immunotherapy and non-selective β-blockers significantly improved overall survival [269].”
Massalee, R., & Cao, X. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1325050 · Cited by 35 · see citing works
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 36 · see citing works
Tumor suppression of novel anti–PD-1 antibodies mediated through CD28 costimulatory pathway
Fenwick, C. W., Loredo-Varela, J.-L., Joo, V., Pellaton, C., Farina, A., Rajah, N., Esteves-Leuenberger, L., Decaillon, T., Suffiotti, M., Noto, A., et al. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20182359 · Cited by 35 · see citing works
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Adrenergic Signaling in Immunotherapy of Cancer: Friend or Foe?
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“Testing melanoma patients makes a lot of sense, because pre-clinical data from mouse melanoma models as well as retrospective data [59] suggest efficacy, also in combination with immunotherapy.”
BackgroundResultGandhi, S., Pandey, M. R., Ammannagari, N., Wang, C., Bucsek, M. J., Hamad, L., Repasky, E. A., & Ernstoff, M. S. (2020) · Immunotherapy · doi:10.2217/imt-2019-0064 · Cited by 33 · see citing works
Self-citationChen, M., Singh, A. K., & Repasky, E. A. (2020) · Cancers · doi:10.3390/cancers12123853 · Cited by 34 · see citing works
Self-citationUnintended Effects of GPCR-Targeted Drugs on the Cancer Phenotype
Cornwell, A. C., & Feigin, M. E. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.10.001 · Cited by 33 · see citing works
“This was further substantiated by a retrospective study of clinical data, which found that pan-β-blocker use was associated with improved survival in metastatic melanoma patients treated with immunotherapy [19].”
ResultHopson, M. B., Lee, S., Accordino, M. K., Trivedi, M. S., Maurer, M., Crew, K. D., Hershman, D. L., & Kalinsky, K. M. (2021) · Breast Cancer Research and Treatment · doi:10.1007/s10549-021-06210-x · Cited by 33 · see citing works
“These ndings are concordant with other recent studies which suggest that concurrent use of propranolol improves tumor response to immunotherapy [26,27].”
ResultNeuroendocrine Factors in Melanoma Pathogenesis
Scheau, C., DRAGHICI, C. C., Ilie, M. A., Lupu, M., Solomon, I., Tampa, M. Ş., Georgescu, S. R., Căruntu, A., Constantin, C., Neagu, M. T., et al. (2021) · Cancers · doi:10.3390/cancers13092277 · Cited by 33 · see citing works
“Moreover, research regarding the use of immunotherapy in melanoma has shown improved survival rates under treatment with beta-blockers in association with dual alfa-programmed death receptor-1 and high dose IL-2 therapy with action on β2-adrenoreceptors [86,87].”
BackgroundStress and cancer. Part II: Therapeutic implications for oncology
Mravec, B., Tibenský, M., & Horváthová, Ľ. (2020) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2020.577312 · Cited by 32 · see citing works
Effect of chronic stress on tumorigenesis and development
Wang, C., Shen, Y., Ni, J., Hu, W., & Yang, Y. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04455-3 · Cited by 31 · see citing works
“Studies also reveals that β-AR antagonists reduce the cardiotoxicity of Trastuzumab [160, 161] and improve the efficacy of immunotherapies [162].”
BackgroundNeurobiology of cancer: Adrenergic signaling and drug repurposing
Dong, Z.-K., Wang, Y., Li, W., & Jin, W. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108750 · Cited by 33 · see citing works
β3-Adrenoceptors as Putative Regulator of Immune Tolerance in Cancer and Pregnancy
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Mellgard, G. S., Patel, V. G., Zhong, X., Joshi, H. N., Qin, Q., Wang, B., Parikh, A. B., Jun, T. W., Alerasool, P., Garcia, P., et al. (2022) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-022-04159-y · Cited by 30 · see citing works
“Similarly, prior retrospective and prospective studies (Kokolus et al. 2018; Gandhi et al. 2021) suggesting enhanced activity of ICB when combined with BB in melanoma, our dataset demonstrated improved rates of disease control among melanoma patients receiving beta blockade.”
BackgroundResultInfluentialNeuroimmunology of cancer and associated symptomology
Scheff, N. N., & Saloman, J. L. (2021) · Immunology and Cell Biology · doi:10.1111/imcb.12496 · Cited by 33 · see citing works
Yan, X., Liu, P., Li, D., Hu, R. Y., Tao, M., Zhu, S., Wu, W., Yang, M., & Qu, X. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109383 · Cited by 29 · see citing works
Kokolus, K. M., Haley, J. S., Koubek, E. J., Gowda, R., Dinavahi, S. S., Sharma, A. K., Claxton, D. F., Helm, K. F., Drabick, J. J., Robertson, G. P., et al. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1539614 · Cited by 28 · see citing works
“checkpoint blockade therapy in pre-clinical models.(14,15) Preclinical studies performed in clinically relevant melanoma models support the idea that combining αPD-1-based immune therapy with targeted therapies, such as mitogen activated protein kinase (MAPK) and phosphoinositide 3 kinase (PI3K) inhibitors, can improv…”
BackgroundSelf-citationWang, Y., Dong, Z.-K., & Jin, W. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02396-6 · Cited by 30 · see citing works
“In addition, in metastatic melanoma patients receiving immunotherapy (e.g., anti-PD-1), adjunctive use of non-selective β-blockers (e.g., propranolol) was associated with reduced recurrence rates and improved overall survival [218].”
β-adrenergic signaling blockade attenuates metastasis through activation of cytotoxic CD4 T cells
Fjæstad, K. Y., Johansen, A. Z., Linder, H., Baker, K. J., Schattefor, M., Czajkowski, N. K., Thorseth, M., Siersbæk, M. S., Kurzay, A., Perez-Penco, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-65048-9 · Cited by 26 · see citing works
Antidiabetics, Anthelmintics, Statins, and Beta-Blockers as Co-Adjuvant Drugs in Cancer Therapy
Gales, L. N., Forsea, L., Mitrea, D., Stefanica, I., Stanculescu, I., Mitrica, R. I., Géorgescu, M., Trifanescu, O. G., Anghel, R. M., & Serbanescu, L. G. (2022) · Medicina · doi:10.3390/medicina58091239 · Cited by 26 · see citing works
“A prospective nonrandomized study of propranolol (80 mg daily) in the adjuvant setting of resected melanoma found an 80% decrease in melanoma relapse [72], but also in metastatic melanoma, the use of specific therapy and nonselective beta-blockers led to better overall survival compared to selective beta-blockers [73].”
BackgroundThe Immune Landscape of Pheochromocytoma and Paraganglioma: Current Advances and Perspectives
Uher, O., Vanova, K. H., Taïeb, D., Calsina, B., Robledo, M., Clifton-Bligh, R. J., & Pacák, K. (2024) · Endocrine Reviews · doi:10.1210/endrev/bnae005 · Cited by 29 · see citing works
Sun, C., Shen, Y., Wang, F., Lu, T., & Zhang, J. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06657-2 · Cited by 27 · see citing works
Farhoumand, L. S., Fiorentzis, M., Kraemer, M. M., Sak, A., Stuschke, M., Rassaf, T., Hendgen-Cotta, U. B., Bechrakis, N. E., & Berchner‐Pfannschmidt, U. (2022) · Cancers · doi:10.3390/cancers14133097 · Cited by 23 · see citing works
Chen, H. Y., Zhao, W., Na’ara, S., Gleber‐Netto, F. O., Xie, T., Ali, S. R., Thompson, Z. M., Buell, J. B., Stafford, H. D., Nagarajan, P., et al. (2023) · JCO Precision Oncology · doi:10.1200/po.22.00490 · Cited by 23 · see citing works
The Impact of Beta Blockers on Survival in Cancer Patients: A Systematic Review and Meta-Analysis
Sharma, A. E., Chan, S., Komorowski, A. S., Cao, X., Gao, Y. K., Kshatri, K., Desai, K., Kuksis, M., Rosen, M. N., Sachdeva, A., et al. (2025) · Cancers · doi:10.3390/cancers17081357 · Cited by 22 · see citing works
“If positive, these will confirm the utility of BBs as an accessible and cost-effective adjunct to existing cancer therapies.”
Remodeling the tumor dormancy ecosystem to prevent recurrence and metastasis
Liang, Y., Chen, W., Zhang, Y., & Li, L. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02328-2 · Cited by 28 · see citing works
Self-citationDestress and do not suppress: targeting adrenergic signaling in tumor immunosuppression
Íñigo-Marco, I., & Alonso, M. M. (2019) · Journal of Clinical Investigation · doi:10.1172/jci133115 · Cited by 22 · see citing works
Filippi, L., Pini, A., Cammalleri, M., Bagnoli, P., & Monte, M. D. (2021) · Medicinal Research Reviews · doi:10.1002/med.21874 · Cited by 21 · see citing works
Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors
Thuru, X., Magnez, R., Bouazzati, H. E., Vergoten, G., Quesnel, B., & Bailly, C. (2022) · Cancers · doi:10.3390/cancers14143368 · Cited by 22 · see citing works
Adrenergic receptor signaling regulates the CD40-receptor mediated anti-tumor immunity
Singh, A., & Ranjan, A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1141712 · Cited by 22 · see citing works
Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity
Switzer, B., Puzanov, I. J., Gandhi, S., & Repasky, E. A. (2023) · Melanoma Research · doi:10.1097/cmr.0000000000000943 · Cited by 22 · see citing works
“Interestingly, blockade of β 2-AR pathways has been observed to enhance the anti-tumoral immune response and improve overall survival in murine models as well as patients with melanoma, breast, and prostate cancer [20–25].”
BackgroundResultInfluentialSelf-citationAutonomic nervous system control of multiple myeloma
Cheng, Y., Sun, F., D’Souza, A., Dhakal, B., Pisano, M. D., Chhabra, S., Stolley, M. R., Hari, P., & Janz, S. (2020) · Blood Reviews · doi:10.1016/j.blre.2020.100741 · Cited by 23 · see citing works
Steinberger, K. J., Bailey, M. T., Gross, A. C., Sumner, L. A., Voorhees, J. L., Crouser, N. J., Curry, J. M., Wang, Y., DeVries, A. C., Marsh, C. B., et al. (2020) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-19-0370 · Cited by 21 · see citing works
“b-blockers have demonstrated beneficial effects in patients with established melanoma including increases in overall survival (45, 46) and reduced disease progression (47).”
BackgroundPropranolol: A “Pick and Roll” Team Player in Benign Tumors and Cancer Therapies
Albiñana, V., Gallardo‐Vara, E., Casado‐Vela, J., Recio-Poveda, L., Botella, L. M., & Cuesta, Á. M. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11154539 · Cited by 21 · see citing works
“Furthermore, new trials have been supporting the synergistic effect of propranolol as an adjuvant in combination therapies with cytotoxic 5-FU [23], TKI sunitinib [75], an anti-PD-1 [76] plus IL-2, the electron transport chain inhibitor, metformin [77], and the glycolysis inhibitor, 2DG [78].”
BackgroundO’Logbon, J., Tarantola, L., Williams, N. R., Mehta, S., Ahmed, A., & Davies, E. (2025) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-025-06262-2 · Cited by 22 · see citing works
Hamy, 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 20 · see citing works
The Role of β-Blockers in Melanoma
GIORGI, V. D., Geppetti, P., Lupi, C., & Benemei, S. (2019) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-019-09876-9 · Cited by 21 · see citing works
“immunotherapy had improved overall survival if they also received β-blockers (Kokolus et al. 2017).”
BackgroundCurrent Therapies and New Targets to Fight Melanoma: A Promising Role for the β3-Adrenoreceptor
Filippi, L., Bruno, G., Domazetovic, V., Favre, C., & Calvani, M. (2020) · Cancers · doi:10.3390/cancers12061415 · Cited by 19 · see citing works
“A recent study observed a significant survival benefit for patients treated with immunotherapy and taking unselective β-blockers compared to either those receiving no β-blockers or β1 selective-blockers [66].”
BackgroundPsychological stress on cancer progression and immunosenescence
Huang, Y., Zhan, Y., & Zhan, Y. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.05.007 · Cited by 19 · see citing works
Wu, L. Y., Hyfte, G. V., Özbek, U., Reincke, M., Gampa, A., Mohamed, Y. I., Nishida, N., Wietharn, B., Amara, S., Lee, P., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1128569 · Cited by 18 · see citing works
“also showed that bAR blockade enhanced the antitumor effect of anti-PD-1 checkpoint inhibitor in a murine model of melanoma (32).”
BackgroundResult
- Authors
- Kokolus, K. M., Zhang, Y., Sivik, J. M., Schmeck, C., Zhu, J., Repasky, E. A., Drabick, J. J., & Schell, T. D.
- Affiliations
- Pennsylvania State University (US)
- Penn State Milton S. Hershey Medical Center (US)
- Roswell Park Comprehensive Cancer Center (US)
- Corresponding author
- Schell, Todd. D.
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2017-12-21
- Volume
- 7
- Issue
- 3
- Pages
- e1405205
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC5790362
- OpenAlex
- W2768592202
- Cited by
- 200
- References
- 51
- Citations by year
- 2026: 30 · 2025: 23 · 2024: 17 · 2023: 31 · 2022: 23 · 2021: 28 · 2020: 22 · 2019: 21 · 2018: 5
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- OncoImmunology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Pennsylvania Department of Health (PDH) (SAP #4100072562)
- HHS | National Institutes of Health (NIH) (CA060395)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- beta-blockers, metastatic melanoma, immunotherapy, beta-adrenergic signaling, anti-PD-1 therapy, interleukin-2, beta2-adrenergic receptor, overall survival, combination therapy, murine melanoma model
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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