STRESS-INDUCED MODULATION OF THE TUMOR MICROENVIRONMENT: MECHANISMS AND IMPLICATIONS FOR CANCER PROGRESSION
DOI:
https://doi.org/10.15407/exp-oncology.2025.02.127Keywords:
stress, tumor microenvironment, cancer progressionAbstract
Chronic stress is one of the key exogenous factors that can significantly affect tumor cell biology by disrupting the regulation of the tumor microenvironment (TME), thereby promoting the manifestation of the malignant process. Activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system induced by stressors leads to the secretion of glucocorticoids and catecholamines, which contribute to the deregulation of microenvironmental components that determine the aggressiveness of malignant neoplasms. This review systematizes the current views on the impact of stress-induced signals on the immune, stromal, vascular, and metabolic components of the TME and analyzes their contribution to the formation of an aggressive tumor phenotype. Particular attention is given to the interplay between neurohumoral stress, the gut, and the intratumoral microbiome, forming a complex networked environment supporting tumor progression. Advancing the understanding of molecular interactions between stress mediators and cellular elements of the TME will provide a foundation for developing innovative therapeutic strategies targeting not only the tumor itself but also minimizing the adverse effects of stress on individual components of the TME.
References
Gold PW, Wong ML. The neuroendocrinology of stress and the importance of a proper balance between the mine- ralocorticoid and glucocorticoid receptors. Mol Psychiatry. 2025;30(1):1-3. https://doi.org/10.1038/s41380-024- 02686-3
Agorastos A, Chrousos GP. The neuroendocrinology of stress: the stress-related continuum of chronic disease deve- lopment. Mol Psychiatry. 2022;27(1):502-513. https://doi.org/10.1038/s41380-021-01224-9
Godoy LD, Rossignoli MT, Delfino-Pereira P, et al. A comprehensive overview on stress neurobiology: basic concepts and clinical implications. Front Behav Neurosci. 2018;12:127. https://doi.org/10.3389/fnbeh.2018.00127
Herman JP, McKlveen JM, Ghosal S, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response.
Compr Physiol. 2016;6(2):603-621. https://doi.org/10.1002/cphy.c150015
Meng LB, Zhang YM, Luo Y, et al. Chronic stress a potential suspect zero of atherosclerosis: a systematic review. Front Cardiovasc Med. 2021;8:738654. https://doi.org/10.3389/fcvm.2021.738654
Aschbacher K, Kornfeld S, Picard M, et al. Chronic stress increases vulnerability to diet-related abdominal fat, oxidative stress, and metabolic risk. Psychoneuroendocrinology. 2014;46:14-22. https://doi.org/10.1016/j.psyneuen.2014.04.003
Morey JN, Boggero IA, Scott AB, Segerstrom SC. Current directions in stress and human immune function. Curr Opin Psychol. 2015;5:13-17. https://doi.org/10.1016/j.copsyc.2015.03.007
Hassamal S. Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories. Front Psychiatry. 2023;14:1130989. https://doi.org/10.3389/fpsyt.2023.1130989
Dhabhar FS, McEwen BS. Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking. Brain Behav Immun. 1997;11(4):286-306. https://doi.org/10.1006/ brbi.1997.0508
Lei Y, Liao F, Tian Y, et al. Investigating the crosstalk between chronic stress and immune cells: implications for enhanced cancer therapy. Front Neurosci. 2023;17:1321176. https://doi.org/10.3389/fnins.2023.1321176
Tian W, Liu Y, Cao C, et al. Chronic stress: impacts on tumor microenvironment and implications for anti-cancer treatments. Front Cell Dev Biol. 2021;9:777018. https://doi.org/10.3389/fcell.2021.777018
Du X, Jiang F, Fan R, Kong J. Impact of stress on tumor progression and the molecular mechanisms of exercise intervention: from psychological stress to tumor immune escape. Psycho-Oncologie. 2025;19(1):3596-3596. https:// doi.org/10.18282/po3596
O’Rourke K, Huddart S. Surgical stress response and cancer outcomes: a narrative review. Dig Med Res. 2020;3:dmr- 20-94. https://doi.org/10.21037/dmr-20-94
Thapa S, Cao X. Nervous regulation: beta-2-adrenergic signaling in immune homeostasis, cancer immunotherapy, and autoimmune diseases. Cancer Immunol Immunother. 2023;72(8):2549-2556. https://doi.org/10.1007/s00262- 023-03445-z
Antoni MH, Dhabhar FS. The impact of psychosocial stress and stress management on immune responses in pa- tients with cancer. Cancer. 2019;125(9):1417-1431. https://doi.org/10.1002/cncr.31943
Qin JF, Jin FJ, Li N, et al. Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB Rep. 2015;48(5):295-300. https://doi.org/10.5483/ bmbrep.2015.48.5.008
Cheng Y, Tang XY, Li YX, et al. Depression-induced neuropeptide Y secretion promotes prostate cancer growth by recruiting myeloid cells. Clin Cancer Res. 2019;25(8):2621-2632. https://doi.org/10.1158/1078-0432.CCR-18-2912
Wu Y, Luo X, Zhou Q, et al. The disbalance of LRP1 and SIRPby psychological stress dampens the clearance of tumor cells by macrophages. Acta Pharm Sin B. 2022;12(1):197-209. https://doi.org/10.1016/j.apsb.2021.06.002
Zhao Y, Jia Y, Shi T, et al. Depression promotes hepatocellular carcinoma progression through a glucocorticoid- mediated upregulation of PD-1 expression in tumor-infiltrating NK cells. Carcinogenesis. 2019;40(9):1132-1141. https://doi.org/10.1093/carcin/bgz017
Varker KA, Terrell CE, Welt M, et al. Impaired natural killer cell lysis in breast cancer patients with high lev- els of psychological stress is associated with altered expression of killer immunoglobin-like receptors. J Surg Res. 2007;139(1):36-44. https://doi.org/10.1016/j.jss.2006.08.037
Glasner A, Avraham R, Rosenne E, et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol. 2010;184(5):2449-2457. https://doi.org/10.4049/jimmunol.0903301
Zadvornyi T, Lukianova N, Borikun T, et al. Mast cells as a tumor microenvironment factor associated with the ag- gressiveness of prostate cancer. Neoplasma. 2022;69(6):1490-1498. https://doi.org/10.4149/neo_2022_221014N1020
Mushii O, Pavlova A, Bazas V, et al. Osteopontin-regulated changes in the mast cell population associated with breast cancer. Exp Oncol. 2024;46(3):209-220. https://doi.org/10.15407/exp-oncology.2024.03.209
Mushii O, Pavlova A, Bazas V, et al. Mast cells as a factor in regulation of breast cancer stromal component asso- ciated with breast cancer aggressiveness. Exp Oncol. 2025;46(4):311-323. https://doi.org/10.15407/exp-oncology. 2024.04.311
Sitte A, Goess R, Tüfekçi T, et al. Correlation of intratumoral mast cell quantity with psychosocial distress in patients with pancreatic cancer: the PancStress study. Sci Rep. 2024;14(1):26285. https://doi.org/10.1038/s41598-024-77010-8
Liu Y, Fang X, Yuan J, et al. The role of corticotropin-releasing hormone receptor 1 in the development of colitisa- ssociated cancer in mouse model. Endocr Relat Cancer. 2014;21(4):639-651. https://doi.org/10.1530/ERC-14-0239
Theoharides TC, Rozniecki JJ, Sahagian G, et al. Impact of stress and mast cells on brain metastases. J Neuroimmu- nol. 2008;205(1-2):1-7. https://doi.org/10.1016/j.jneuroim.2008.09.014
Esposito P, Chandler N, Kandere K, et al. Corticotropin-releasing hormone and brain mast cells regulate blood- brain-barrier permeability induced by acute stress. J Pharmacol Exp Ther. 2002;303(3):1061-1066. https://doi. org/10.1124/jpet.102.038497
Baldwin AL. Mast cell activation by stress. Methods Mol Biol. 2006;315:349-360. https://doi.org/10.1385/1-59259- 967-2:349
Kurashima Y, Kiyono H, Kunisawa J. Pathophysiological role of extracellular purinergic mediators in the control of intestinal inflammation. Med Inflamm. 2015;2015:427125. https://doi.org/10.1155/2015/427125
Wang L, Sikora J, Hu L, et al. ATP release from mast cells by physical stimulation: a putative early step in activation of acupuncture points. Evid Based Complement Alternat Med. 2013;2013:350949. https://doi.org/10.1155/2013/350949
Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends Immunol. 2016;37(12):855-865. https://doi. org/10.1016/j.it.2016.09.006
Sommershof A, Scheuermann L, Koerner J, Groettrup M. Chronic stress suppresses anti-tumor TCD8+ responses and tumor regression following cancer immunotherapy in a mouse model of melanoma. Brain Behav Immun. 2017;65:140-149. https://doi.org/10.1016/j.bbi.2017.04.021
Maestroni GJ, Mazzola P. Langerhans cells beta 2-adrenoceptors: role in migration, cytokine production, Th priming and contact hypersensitivity. J Neuroimmunol. 2003;144(1-2):91-99. https://doi.org/10.1016/j.jneuroim.2003.08.039
Matyszak MK, Citterio S, Rescigno M, Ricciardi-Castagnoli P. Differential effects of corticosteroids during differ- ent stages of dendritic cell maturation. Eur J Immunol. 2000;30(4):1233-1242. https://doi.org/10.1002/(SICI)1521- 4141(200004)30:4<1233::AID-IMMU1233>3.0.CO;2-F
Ahmed H, Mahmud AR, Siddiquee MF, et al. Role of T cells in cancer immunotherapy: opportunities and chal- lenges. Cancer Pathog Ther. 2022;1(2):116-126. https://doi.org/10.1016/j.cpt.2022.12.002
de Visser KE, Joyce JA. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth.
Cancer Cell. 2023;41(3):374-403. https://doi.org/10.1016/j.ccell.2023.02.016
Colon-Echevarria CB, Lamboy-Caraballo R, Aquino-Acevedo AN, Armaiz-Pena GN. Neuroendocrine regulation of tumor-associated immune cells. Front Oncol. 2019;9:1077. https://doi.org/10.3389/fonc.2019.01077
Budiu RA, Vlad AM, Nazario L, et al. Restraint and social isolation stressors differentially regulate adaptive im- munity and tumor angiogenesis in a breast cancer mouse model. Cancer Clin Oncol. 2017;6(1):12-24. https://doi. org/10.5539/cco.v6n1p12
Nissen MD, Sloan EK, Mattarollo SR. β-adrenergic signaling impairs antitumor CD8+ T-cell responses to B-cell lym- phoma immunotherapy. Cancer Immunol Res. 2018;6(1):98-109. https://doi.org/10.1158/2326-6066.CIR-17-0401
Acharya N, Madi A, Zhang H, et al. Endogenous glucocorticoid signaling regulates CD8+ T cell differentiation and development of dysfunction in the tumor microenvironment. Immunity. 2020;53(3):658-671.e6. https://doi. org/10.1016/j.immuni.2020.08.005
Geng Q, Li L, Shen Z, et al. Norepinephrine inhibits CD8+ T-cell infiltration and function, inducing anti-PD-1 mAb resistance in lung adenocarcinoma. Br J Cancer. 2023;128(7):1223-1235. https://doi.org/10.1038/s41416-022-02132-7
Guereschi MG, Araujo LP, Maricato JT, et al. Beta2-adrenergic receptor signaling in CD4+ Foxp3+ regulatory T cells enhances their suppressive function in a PKA-dependent manner. Eur J Immunol. 2013;43(4):1001-1012. https://doi.org/10.1002/eji.201243005
Qiao G, Chen M, Mohammadpour H, et al. Chronic adrenergic stress contributes to metabolic dysfunction and an exhausted phenotype in T cells in the tumor microenvironment. Cancer Immunol Res. 2021;9(6):651-664. https:// doi.org/10.1158/2326-6066.CIR-20-0445
Kume H, Homma Y, Shinohara N, et al. Perinephric invasion as a prognostic factor in non-metastatic renal cell car- cinoma: analysis of a nation-wide registry program. Jpn J Clin Oncol. 2019;49(8):772-779. https://doi.org/10.1093/ jjco/hyz054
Iñigo-Marco I, Alonso MM. Destress and do not suppress: targeting adrenergic signaling in tumor immunosup- pression. J Clin Invest. 2019;129(12):5086-5088. https://doi.org/10.1172/JCI133115
An J, Feng L, Ren J, et al. Chronic stress promotes breast carcinoma metastasis by accumulating myeloid-derived suppressor cells through activating β-adrenergic signaling. Oncoimmunology. 2021;10(1):2004659. https://doi.org/ 10.1080/2162402X.2021.2004659
Cao M, Huang W, Chen Y, et al. Chronic restraint stress promotes the mobilization and recruitment of myeloid- derived suppressor cells through β-adrenergic-activated CXCL5-CXCR2-Erk signaling cascades. Int J Cancer. 2021;149(2):460-472. https://doi.org/10.1002/ijc.33552
Yang EV, Kim SJ, Donovan EL, et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human mela- noma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun. 2009;23(2):267-275. https://doi.org/10.1016/j.bbi.2008.10.005
Bouchard LC, Antoni MH, Blomberg BB, et al. Postsurgical depressive symptoms and proinflammatory cytokine elevations in women undergoing primary treatment for breast cancer. Psychosom Med. 2016;78(1):26-37. https:// doi.org/10.1097/PSY.0000000000000261
Lukianova N, Mushii O, Zadvornyi T, Chekhun V. Development of an algorithm for biomedical image analysis of the spatial organization of collagen in breast cancer tissue of patients with different clinical status. FEBS Open Bio. 2024;14(4):675-686. https://doi.org/10.1002/2211-5463.13773
Lukianova N, Zadvornyi T, Mushii O, et al. Evaluation of diagnostic algorithm based on collagen organization parameters for breast tumors. Exp Oncol. 2022;44(4):281-286. https://doi.org/10.32471/exp-oncology.2312-8852. vol-44-no-4.19137
Hondermarck H, Jobling P. The sympathetic nervous system drives tumor angiogenesis. Trends Cancer. 2018;4(2):93- 94. https://doi.org/10.1016/j.trecan.2017.11.008
Zhao Y, Shen M, Wu L, et al. Stromal cells in the tumor microenvironment: accomplices of tumor progression? Cell Death Dis. 2023;14(9):587. https://doi.org/10.1038/s41419-023-06110-6
Chen X, Song E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov. 2019;18(2):99- 115. https://doi.org/10.1038/s41573-018-0004-1
Shiga K, Hara M, Nagasaki T, et al. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers (Basel). 2015;7(4):2443-2458. https://doi.org/10.3390/cancers7040902
Nagaraja AS, Dood RL, Armaiz-Pena G, et al. Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens. JCI Insight. 2017;2(16):e93076. https://doi.org/10.1172/jci.insight.93076
Chekhun V, Mushii O, Zadvornyi T, et al. Features of COL1A1 expression in breast cancer tissue of young patients.
Exp Oncol. 2023;45(3):351-363. https://doi.org/10.15407/exp-oncology.2023.03.351
Lukianova N, Mushii O, Borikun T, et al. Pattern of MMP2 and MMP9 expression depends on breast cancer pa- tients’ age. Exp Oncol. 2023;45(1):17-27. https://doi.org/10.15407/exp-oncology.2023.01.017
Cheng Y, Gao XH, Li XJ, et al. Depression promotes prostate cancer invasion and metastasis via a sympathe- ticcAMP-FAK signaling pathway. Oncogene. 2018;37(22):2953-2966. https://doi.org/10.1038/s41388-018-0177-4
Wu X, Liu BJ, Ji S, et al. Social defeat stress promotes tumor growth and angiogenesis by upregulating vascular en- dothelial growth factor/extracellular signal-regulated kinase/matrix metalloproteinase signaling in a mouse model of lung carcinoma. Mol Med Rep. 2015;12(1):1405-1412. https://doi.org/10.3892/mmr.2015.3559
Thaker PH, Han LY, Kamat AA, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12(8):939-944. https://doi.org/10.1038/nm1447
Yang EV, Sood AK, Chen M, et al. Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res. 2006;66(21):10357-10364. https://doi.org/10.1158/0008-5472.CAN-06-2496
Huang Z, Li G, Zhang Z, et al. β2AR-HIF-1-CXCL12 signaling of osteoblasts activated by isoproterenol promotes mi- gration and invasion of prostate cancer cells. BMC Cancer. 2019;19(1):1142. https://doi.org/10.1186/s12885-019-6301-1
Hulsurkar M, Li Z, Zhang Y, et al. Beta-adrenergic signaling promotes tumor angiogenesis and prostate cancer pro- gression through HDAC2-mediated suppression of thrombospondin-1. Oncogene. 2017;36(11):1525–1536. https:// doi.org/10.1038/onc.2016.319
Lu Y, Zhao H, Liu Y, et al. Chronic stress activates PlexinA1/VEGFR2-JAK2-STAT3 in vascular endothelial cells to promote angiogenesis. Front Oncol. 2021;11:709057. https://doi.org/10.3389/fonc.2021.709057
Zhou J, Liu Z, Zhang L, et al. Activation of β2-adrenergic receptor promotes growth and angiogenesis in breast cancer by down-regulating PPARγ. Cancer Res Treat. 2020;52(3):830-847. https://doi.org/10.4143/crt.2019.510
Le CP, Nowell CJ, Kim-Fuchs C, et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat Commun. 2016;7:10634. https://doi.org/10.1038/ncomms10634
Shan T, Cui X, Li W, et al. Novel regulatory program for norepinephrine-induced epithelial-mesenchymal transi- tion in gastric adenocarcinoma cell lines. Cancer Sci. 2014;105(7):847-856. https://doi.org/10.1111/cas.12438
Zhang P, Liu Y, Feng Y, Gao S. SNAIL gene inhibited by hypoxia-inducible factor 1(HIF-1) in epithelial ovarian cancer. Int J Immunopathol Pharmacol. 2016;29(3):364-375. https://doi.org/10.1177/0394632016641423
Perego M, Tyurin VA, Tyurina YY, et al. Reactivation of dormant tumor cells by modified lipids derived from stress- activated neutrophils. Sci Transl Med. 2020;12(572):eabb5817. https://doi.org/10.1126/scitranslmed.abb5817
Cui B, Luo Y, Tian P, et al. Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast can- cer stem-like cells. J Clin Invest. 2019;129(3):1030-1046. https://doi.org/10.1172/JCI121685
Aboelella NS, Brandle C, Kim T, Ding ZC, Zhou G. Oxidative stress in the tumor microenvironment and its rel- evance to cancer immunotherapy. Cancers (Basel). 2021;13(5):986. https://doi.org/10.3390/cancers13050986
Zahalka AH, Arnal-Estapé A, Maryanovich M, et al. Adrenergic nerves activate an angio-metabolic switch in pros- tate cancer. Science. 2017;358(6361):321-326. https://doi.org/10.1126/science.aah5072
Seebacher NA, Krchniakova M, Stacy AE, et al. Tumour microenvironment stress promotes the development of drug resistance. Antioxidants (Basel). 2021;10(11):1801. https://doi.org/10.3390/antiox10111801
Zemanová N, Anzenbacher P, Zapletalová I, et al. The role of the microbiome and psychosocial stress in the expres- sion and activity of drug metabolizing enzymes in mice. Sci Rep. 2020;10(1):8529. https://doi.org/10.1038/s41598- 020-65595-9
Yang L, Li A, Wang Y, Zhang Y. Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy. Signal Transduct Target Ther. 2023;8(1):35. https://doi.org/10.1038/s41392-022-01304-4
Zhang T, Gao G, Sakandar HA, et al. Gut dysbiosis in pancreatic diseases: a causative factor and a novel therapeutic target. Front Nutr. 2022;9:814269. https://doi.org/10.3389/fnut.2022.814269
Leigh SJ, Uhlig F, Wilmes L, et al. The impact of acute and chronic stress on gastrointestinal physiology and func- tion: a microbiota-gut-brain axis perspective. J Physiol. 2023;601(20):4491-4538. https://doi.org/10.1113/JP281951
Niu L, Gao M, Wen S, et al. Effects of catecholamine stress hormones norepinephrine and epinephrine on growth, antimicrobial susceptibility, biofilm formation, and gene expressions of enterotoxigenic Escherichia coli. Int J Mol Sci. 2023;24(21):15646. https://doi.org/10.3390/ijms242115646
Cao Q, Zhao M, Su Y, et al. Chronic stress dampens Lactobacillus johnsonii-mediated tumor suppression to enhance colorectal cancer progression. Cancer Res. 2024;84(5):771-784. https://doi.org/10.1158/0008-5472.CAN-22-3705
He Z, Liu C, Lan P. Association of gut microbe and stress-related cancer metastasis and oleic acid degradation.
J Clin Oncol. 2024;42:e15517. https://doi.org/10.1200/JCO.2024.42.16_suppl.e15517
Zhao L, Hou X, Feng Y, et al. A chronic stress-induced microbiome perturbation, highly enriched in Ruminococ- caceae_UCG-014, promotes colorectal cancer growth and metastasis. Int J Med Sci. 2024;21(5):882–895. https:// doi.org/10.7150/ijms.90612
Ye L, Hou Y, Hu W, et al. Repressed Blautia-acetate immunological axis underlies breast cancer progression pro- moted by chronic stress. Nat Commun. 2023;14(1):6160. https://doi.org/10.1038/s41467-023-41817-2
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Experimental Oncology
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
