Histamine signaling and antihistamines in cancer progression and immunotherapy: current perspectives

Abstract

Despite advances in treatment, cancer remains a leading cause of death worldwide. Immunotherapy has revolutionized clinical oncology, extending survival for many patients with advanced disease; however, low response rates in certain cancers remain a major challenge. Histamine, traditionally known as an inflammatory and allergic mediator, has recently been implicated in key aspects of cancer biology. Through binding to its receptors, histamine influences cancer cell proliferation, migration, invasion, apoptosis, and drug resistance. Furthermore, emerging evidence suggests that combining antihistamines with immunotherapeutic agents may improve patient survival. This review focuses on the roles of histamine and its receptors in modulating cancer progression and explores how antihistamines might interfere with these processes. We also discuss the significance of histamine within the tumor microenvironment and propose how modulating histamine signaling could enhance the efficacy of immunotherapy. These insights aim to guide the rational design of future chemo-immunotherapy combinations.

Keywords

Histamine / Histamine receptor / Antihistamine / Tumor microenvironment / Immunotherapy / Cancer progression

References

[1] Yu WD, Sun G, Li J, Xu J, Wang X. Mechanisms and therapeutic potentials of cancer immunotherapy in combination with radiotherapy and/or chemotherapy. Cancer Lett. 2019; 45: 66-70.

[2] Keenan TE, Tolaney SM. Role of immunotherapy in triple—negative breast cancer. J Natl Compr Canc Netw. 2020; 18: 479-489.

[3] Jiang Z, et al. Toripalimab plus nab—paclitaxel in metastatic or recurrent triple—negative breast cancer: a randomized phase 3 trial. Nat Med. 2024; 30: 249-256.

[4] Zhang D, Zhao J, Zhang Y, Jiang H, Liu D. Revisiting immune checkpoint inhibitors: new strategies to enhance efficacy and reduce toxicity. Front Immunol. 2024; 15: 1490129.

[5] Nguyen PL, Cho J. Pathophysiological roles of histamine receptors in cancer progression: implications and perspectives as potential molecular targets. Biomolecules. 2021; 11: 1232.

[6] Smolinska S, Winiarska E, Globinska A, Jutel M. Histamine: a mediator of intestinal disorders—a review. Metabolites. 2022; 12: 895.

[7] Massari NA, Nicoud MB, Medina VA. Histamine receptors and cancer pharmacology: an update. Br J Pharmacol. 2020; 177: 516-538.

[8] Shulpekova YO, et al. Food intolerance: the role of histamine. Nutrients. 2021; 13: 3207.

[9] Obara I, Telezhkin V, Alrashdi I, Chazot PL. Histamine, histamine receptors, and neuropathic pain relief. Br J Pharmacol. 2020; 177: 580-599.

[10] Tiligada E, Ennis M. Histamine pharmacology: from Sir Henry Dale to the 21st century. Br J Pharmacol. 2020; 177: 469-489.

[11] Fukasawa T, et al. Pharmacotherapy of itch—antihistamines and histamine receptors as G protein—coupled receptors. Int J Mol Sci. 2022; 23: 6579.

[12] Sgambellone S, Lucarini L, Lanzi C, Masini E. Novel insight of histamine and its receptor ligands in glaucoma and retina neuroprotection. Biomolecules. 2021; 11: 1186.

[13] Neumann J, Hofmann B, Kirchhefer U, Dhein S, Gergs U. Function and role of histamine H1 receptor in the mammalian heart. Pharmaceuticals. 2023; 16: 734.

[14] Saheera S, Potnuri AG, Guha A, Palaniyandi SS, Thandavarayan RA. Histamine 2 receptors in cardiovascular biology: a friend for the heart. Drug Discov Today. 2022; 27: 234-245.

[15] Abdulrazzaq YM, Bastaki SMA, Adeghate E. Histamine H3 receptor antagonists — roles in neurological and endocrine diseases and diabetes mellitus. Biomed Pharmacother. 2022; 150: 112947.

[16] Mehta P, et al. Enigmatic histamine receptor H4 for potential treatment of multiple inflammatory, autoimmune, and related diseases. Life. 2020; 10: 50.

[17] Goradel NH, Najafi M, Salehi E, Farhood B, Mortezaee K. Cyclooxygenase—2 in cancer: a review. J Cell Physiol. 2019; 234(5): 5683-5699.

[18] Huang WC, et al. Histamine regulates cyclooxygenase 2 gene activation through Orai1—mediated NFκB activation in lung cancer cells. Cell Calcium. 2011; 50: 27-35.

[19] Cianchi F, et al. The role of cyclooxygenase—2 in mediating the effects of histamine on cell proliferation and vascular endothelial growth factor production in colorectal cancer. Clin Cancer Res. 2005; 11: 6807-6815.

[20] Chen J, et al. Glioblastoma stem cell—specific histamine secretion drives pro—angiogenic tumor microenvironment remodeling. Cell Stem Cell. 2022; 29: 1531-1546.e7.

[21] Galarza TE, et al. Histamine prevents radiation—induced mesenchymal changes in breast cancer cells. Pharmacol Res. 2016; 111: 731-739.

[22] Wang ZY, et al. Nerve growth factor and receptors are significantly affected by histamine stimulus through H1 receptor in pancreatic carcinoma cells. Mol Med Rep. 2010; 3(1): 103-109.

[23] Kim HJ, Lee PCW, Hong JH. Lamin—A/C Is modulated by the involvement of histamine—mediated calcium/calmodulin—dependent kinase II in lung cancer cells. Int J Mol Sci. 2022; 23: 9075.

[24] Grimm M, et al. Prognostic value of histamine H1 receptor expression in oral squamous cell carcinoma. Clin Oral Invest. 2013; 17: 949-955.

[25] Zhao J, et al. Upregulation of histamine receptor H1 promotes tumor progression and contributes to poor prognosis in hepatocellular carcinoma. Oncogene. 2020; 39: 1724-1738.

[26] Shi Z, et al. Loss of H2R signaling disrupts neutrophil homeostasis and promotes inflammation—associated colonic tumorigenesis in mice. Cell Mol Gastroenterol Hepatol. 2022; 13(3): 717-737.

[27] Chen J, Hu X. Inhibition of histamine receptor H3R suppresses prostate cancer growth, invasion and increases apoptosis via the AR pathway. Oncol Lett. 2018; 16(4): 4921-4928.

[28] Yu D, et al. Upregulated histamine receptor H3 promotes tumor growth and metastasis in hepatocellular carcinoma. Oncol Rep. 2019; 41(6): 3347-3354.

[29] Zhao Y, et al. Inhibition of histamine receptor H3 suppresses the growth and metastasis of human non—small cell lung cancer cells via inhibiting PI3K/Akt/mTOR and MEK/ERK signaling pathways and blocking EMT. Acta Pharmacol Sin. 2021; 42: 1288-1297.

[30] He GH, et al. Activation of histamine H4 receptor suppresses the proliferation and invasion of esophageal squamous cell carcinoma via both metabolism and non—metabolism signaling pathways. J Mol Med. 2018; 96: 951-964.

[31] Fang Z, et al. Attenuated expression of HRH4 in colorectal carcinomas: a potential influence on tumor growth and progression. BMC Cancer. 2011; 11: 195.

[32] Salem A, et al. Histamine H4 receptor signalling in tongue cancer and its potential role in oral carcinogenesis — a short report. Cell Oncol. 2017; 40: 621-630.

[33] Speisky D, et al. Histamine H4 receptor expression in triple—negative breast cancer: an exploratory study. J Histochem Cytochem. 2022; 70: 311-322.

[34] Kraus FBT, et al. Expression pattern and prognostic potential of histamine receptors in epithelial ovarian cancer. J Cancer Res Clin Oncol. 2023; 149: 2501-2511.

[35] Galarza TE, Táquez Delgado MA, Mohamad NA, Martín GA, Cricco GP. Histamine H4 receptor agonists induce epithelial—mesenchymal transition events and enhance mammosphere formation via Src and TGF—β signaling in breast cancer cells. Biochem Pharmacol. 2020; 180: 114177.

[36] Schirmer B, et al. Genetic deficiency of the histamine H4—receptor reduces experimental colorectal carcinogenesis in mice. Cancers. 2020; 12: 912.

[37] He GH, et al. Polymorphisms of human histamine receptor H4 gene are associated with breast cancer in Chinese Han population. Gene. 2013; 519: 260-265.

[38] Cai WK, et al. The HRH4 rs11662595 mutation is associated with histamine H4 receptor dysfunction and with increased epithelial—to—mesenchymal transition progress in non—small cell lung cancer. Biochim Biophys Acta (BBA) — Mol Basis Dis. 2017; 1863: 2954-2963.

[39] Ramos—Jiménez J, et al. Histamine augments β2—adrenoceptor—induced cyclic AMP accumulation in human prostate cancer cells DU—145 independently of known histamine receptors. Biochem Pharmacol. 2007; 73: 814-823.

[40] Liu M, et al. Apigenin inhibits the histamine—induced proliferation of ovarian cancer cells by downregulating ERα/ERβ expression. Front Oncol. 2021; 11: 682917.

[41] Zhang E, et al. Apigenin inhibits histamine—induced cervical cancer tumor growth by regulating estrogen receptor expression. Molecules. 2020; 25: 1960.

[42] Hindmarch I. CNS effects of antihistamines: is there a third generation of non—sedative drugs? Clin Exp Allergy Rev. 2002; 2: 26-31.

[43] Liu X, et al. Loratidine is associated with improved prognosis and exerts antineoplastic effects via apoptotic and pyroptotic crosstalk in lung cancer. J Exp Clin Cancer Res. 2024; 43: 5.

[44] Fritz I, Wagner P, Broberg P, Einefors R, Olsson H. Desloratadine and loratadine stand out among common H1—antihistamines for association with improved breast cancer survival. Acta Oncol. 2020; 59(9): 1103.

[45] Fritz I, et al. Desloratadine and loratadine use associated with improved melanoma survival. Allergy. 2020; 75: 2096-2099.

[46] Fritz I, Wagner P, Olsson H. Improved survival in several cancers with use of H1—antihistamines desloratadine and loratadine. Transl Oncol. 2021; 14: 101029.

[47] Ma J, et al. Desloratadine, a novel antigrowth reagent for bladder cancer. Technol Cancer Res Treat. 2020; 19: 1533033820926591.

[48] Baniya MK, Kim EH, Chun KS. Terfenadine, a histamine H1 receptor antagonist, induces apoptosis by suppressing STAT3 signaling in human colorectal cancer HCT116 cells. Front Pharm. 2024; 15: 1418266.

[49] Wang WT, et al. Terfenadine induces anti—proliferative and apoptotic activities in human hormone—refractory prostate cancer through histamine receptor—independent Mcl—1 cleavage and Bak up—regulation. Naunyn—Schmiedeberg’s Arch Pharm. 2014; 387: 33-45.

[50] Matsushita M, et al. High—fat diet promotes prostate cancer growth through histamine signaling. Int J Cancer. 2022; 151: 623-636.

[51] Jiang CG, Liu FR, Yu M, Li JB, Xu HM. Cimetidine induces apoptosis in gastric cancer cells in vitro and inhibits tumor growth in vivo. Oncol Rep. 2010; 23(3): 693-700.

[52] Ali AH, et al. The effect of perioperative cimetidine administration on time to colorectal cancer recurrence. Am J Ther. 2018; 25: e405-e411.

[53] Natori T, Sata M, Nagai R, Makuuchi M. Cimetidine inhibits angiogenesis and suppresses tumor growth.Biomed Pharmacother. 2005; 59: 56-60.

[54] Ibrahim SSA, El—Aal SAA, Reda AM, Achy SE, Shahine Y. Anti—neoplastic action of cimetidine/Vitamin C on histamine and the PI3K/AKT/mTOR pathway in Ehrlich breast cancer. Sci Rep. 2022; 12: 11514.

[55] Ospital IA, et al. Therapeutic potential of LINS01 histamine H3 receptor antagonists as antineoplastic agents for triple negative breast cancer. Biomed Pharmacother. 2024; 174: 116527.

[56] Tanaka S, Sakaguchi M, Yoneyama H, Usami Y, Harusawa S. Histamine H3 receptor antagonist OUP—186 attenuates the proliferation of cultured human breast cancer cell lines. Biochem Biophys Res Commun. 2016; 480: 479-485.

[57] Meng F, et al. The H4 histamine receptor agonist, clobenpropit, suppresses human cholangiocarcinoma progression by disruption of epithelial mesenchymal transition and tumor metastasis. Hepatology. 2011; 54: 1718-1728.

[58] Kay EJ, Zanivan S. The tumor microenvironment is an ecosystem sustained by metabolic interactions. Cell Rep. 2025; 44: 115432.

[59] Wang L, et al. Advances in targeting tumor microenvironment for immunotherapy. Front Immunol. 2024; 15: 1472772.

[60] Zhang X, et al. Histamine—related genes participate in the establishment of an immunosuppressive microenvironment and impact the immunotherapy response in hepatocellular carcinoma. Clin Exp Med. 2024; 24: 129.

[61] Tomita K, Okabe S. Exogenous histamine stimulates colorectal cancer implant growth via immunosuppression in mice. J Pharmacol Sci. 2005; 97: 116-123.

[62] Nicoud MB, et al. Study of the antitumour effects and the modulation of immune response by histamine in breast cancer. Br J Cancer. 2020; 122: 348-360.

[63] Li J, et al. PD—1+ mast cell enhanced by PD—1 blocking therapy associated with resistance to immunotherapy. Cancer Immunol Immunother. 2023; 72: 633-645.

[64] Li H, et al. The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1. Cancer Cell. 2022; 40: 36-52.e9.

[65] Zhong P, et al. Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC—I expression in pancreatic cancer cells. J Exp Clin Cancer Res. 2024; 43: 138.

[66] Liu P, Kroemer G, Kepp O. Histamine antagonists promote cancer immunosurveillance. Oncoimmunology. 2023; 12(1): 2242211.

[67] Nicoud MB, et al. Impact of histamine H4 receptor deficiency on the modulation of T cells in a murine breast cancer model. Cancer Immunol Immunother. 2021; 70: 233-244.

[68] Sterle HA, et al. Immunomodulatory role of histamine H4 receptor in breast cancer. Br J Cancer. 2019; 120: 128-138.

[69] Maruyama Y, et al. Combination therapy with cetirizine and anti—PD—1 antibody suppresses colitis—induced colon tumor formation in mice. Eur J Pharm. 2025; 999: 177704.

[70] Kuo FC, et al. Cimetidine attenuates therapeutic effect of anti—PD—1 and anti—PD—L1 and modulates tumor microenvironment in colon cancer. Biomedicines. 2024; 12: 697.

[71] Hellstrand K, et al. Alleviating oxidative stress in cancer immunotherapy: a role for histamine? Med Oncol. 2000; 17: 258-269.

[72] Romero AI, et al. Post—consolidation immunotherapy with histamine dihydrochloride and interleukin—2 in AML. Scand J Immunol. 2009; 70: 194-205.

[73] Nilsson MS, et al. Complete remission after the first cycle of induction chemotherapy determines the clinical efficacy of relapse—preventive immunotherapy in acute myeloid leukaemia. Br J Haematol. 2020; 188(4): e49-e53.

[74] Middleton M, et al. Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients: implications for combined immunotherapy with interleukin—2. J Clin Pharma. 2002; 42: 774-781.

[75] Brune M. Improved leukemia—free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin—2 in acute myeloid leukemia: results of a randomized phase 3 trial. Blood. 2006; 108: 88-96.

[76] Grauers Wiktorin H, et al. Impact of IL—1β and the IL—1R antagonist on relapse risk and survival in AML patients undergoing immunotherapy for remission maintenance. OncoImmunology. 2021; 10: 1944538.

[77] Donskov F, et al. Two randomised phase II trials of subcutaneous interleukin—2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma. Br J Cancer. 2005; 93: 757-762.

[78] Donskov F, Hokland M, Marcussen N, Torp Madsen HH, Von Der Maase H. Monocytes and neutrophils as ‘bad guys’ for the outcome of interleukin—2 with and without histamine in metastatic renal cell carcinoma — results from a randomised phase II trial. Br J Cancer. 2006; 94: 218-226.

[79] Agarwala SS, et al. Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin—2 versus interleukin—2 alone in patients with metastatic melanoma. J Clin Oncol. 2002; 20(1): 125-133.

[80] Schmidt H, et al. A phase II study of outpatient subcutaneous histamine dihydrochloride, interleukin—2 and interferon—α in patients with metastatic melanoma. Ann Oncol. 2002; 13: 1919-1924.

[81] Donskov F, et al. Outpatient treatment with subcutaneous histamine dihydrochloride in combination with interleukin—2 and interferon—α in patients with metastatic renal cell carcinoma: results of an open single—armed multicentre phase II study. Ann Oncol. 2002; 13: 441-449.

[82] Lindnér P, Rizell M, Mattsson J, Hellstrand K, Naredi P. Combined treatment with histamine dihydrochloride, interleukin—2 and interferon—alpha in patients with metastatic melanoma. Anticancer Res. 2004; 24(3b): 1837-1842.

[83] Middleton M, et al. Results of a multicenter randomized study to evaluate the safety and efficacy of combined immunotherapy with interleukin—2, interferon—α2b and histamine dihydrochloride versus dacarbazine in patients with stage IV melanoma. Ann Oncol. 2007; 18: 1691-1697.

[84] Zhang WH, et al. Association of concomitant H1 antihistamine and immune checkpoint inhibitor therapy on survival outcome and safety in patients with advanced primary lung cancer: a cohort study. Transl Lung Cancer Res. 2024; 13: 2787-2801.

[85] Leung Y, et al. Concomitant usage of H1—antihistamines and immune checkpoint inhibitors on cancer patient survival. Cancer Med. 2025; 14: e70583.

[86] Mallardo D, et al. Concomitant medication of cetirizine in advanced melanoma could enhance anti—PD—1 efficacy by promoting M1 macrophages polarization. J Transl Med. 2022; 20: 436.

[87] Fallara G, et al. Concomitant antihistamine administration is associated with improved survival outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with atezolizumab. Analysis of individual participant data from IMvigor210 and IMvigor211. Urol Oncol. 2025; 43: 188.e9-188.e17.

[88] Chiang CH, et al. Efficacy of cationic amphiphilic antihistamines on outcomes of patients treated with immune checkpoint inhibitors. Eur J Cancer. 2022; 174: 1-9.