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Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice
Open accessAbstract
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.117”
From Gut dysbiosis in oncology: a risk factor for immunoresistance (2026) · cites this paper as [117]
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“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
“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
“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 33
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 29
“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
β3-Adrenoceptors as Putative Regulator of Immune Tolerance in Cancer and Pregnancy
Calvani, M., Dabraio, A., Subbiani, A., Buonvicino, D., Gregorio, V. D., Mannurita, S. C., Pini, A., Nardini, P., Favre, C., & Filippi, L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.02098 · Cited by 30
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
“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
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
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
“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 32
“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 27
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 28
“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 31
Gut dysbiosis in oncology: a risk factor for immunoresistance
(2026) · doi:10.1038/s41422-025-01212-6 · Cited by 24
Sun, C., Shen, Y., Wang, F., Lu, T., & Zhang, J. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06657-2 · Cited by 29
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 24
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
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
“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 29
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
Filippi, L., Pini, A., Cammalleri, M., Bagnoli, P., & Monte, M. D. (2021) · Medicinal Research Reviews · doi:10.1002/med.21874 · Cited by 24
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
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
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 23
“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 24
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
“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
“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
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 22
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
“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 20
“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
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
“also showed that bAR blockade enhanced the antitumor effect of anti-PD-1 checkpoint inhibitor in a murine model of melanoma (32).”
BackgroundResult
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › 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
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