Int J Stomatol ›› 2026, Vol. 53 ›› Issue (6): 884-894.doi: 10.7518/gjkq.2026614

• Review • Previous Articles    

Neuroimmunology in the progression of salivary adenoid cystic carcinoma

Jiarong Wang(),Yaling Tang()   

  1. State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
  • Received:2025-04-14 Revised:2026-02-25 Online:2026-11-01 Published:2026-10-29
  • Contact: Yaling Tang E-mail:wjr202427@163.com;tangyaling@scu.edu.cn
  • Supported by:
    Clinical Research Program of West China Hospital of Stomatology, Sichuan University(LCYJ-MS-202308)

Abstract:

Salivary adenoid cystic carcinoma (SACC) is a common malignant salivary gland tumor characterized by its propensity for perineural invasion and poor prognosis in advanced stages. Recent advancements in neuroimmunology have highlighted the remarkably role of neural-immune interactions in tumor regulation. However, the specific neuroimmunological mechanisms underlying SACC remain to be elucidated. This review aims to summarize potential neuroimmunological mechanisms in SACC by examining the interactions between neural and immune cells and the roles of neural and immune factors, thereby identifying potential therapeutic targets for future research.

Key words: neuroimmunology, salivary adenoid cystic carcinoma, perineural invasion, tumor microenvironment, Schwann cells

CLC Number: 

  • R739.87

TrendMD: 

Fig 1

Selected immunomodulatory mechanisms of SCs in the tumor microenvironment"

[1] 高岩. 口腔组织病理学[M]. 8版. 北京: 人民卫生出版社, 2020.
Gao Y. Oral histology and pathology[M]. 8th ed. Beijing: People’s Medical Publishing House, 2020.
[2] 胡宜佳, 田野, 宋士玉. 唾液腺复发或转移性腺样囊性癌的治疗进展[J]. 中华放射肿瘤学杂志, 2023, 32(10) : 934-938.
Hu YJ, Tian Y, Song SY. Advances in treatment of recurrent and/or metastatic adenoid cystic carcinoma of salivary glands[J]. Chin J Radiat Oncol, 2023, 32(10): 934-938.
[3] Liebig C, Ayala G, Wilks JA, et al. Perineural invasion in cancer: a review of the literature[J]. Cancer, 2009, 115(15): 3379-3391.
[4] Yang MW, Tao LY, Jiang YS, et al. Perineural invasion reprograms the immune microenvironment th-rough cholinergic signaling in pancreatic ductal adenocarcinoma[J]. Cancer Res, 2020, 80(10): 1991-2003.
[5] Cavaillon JM. Once upon a time, inflammation[J]. J Venom Anim Toxins Incl Trop Dis, 2021, 27:e20200147.
[6] Besedovsky H, Sorkin E. Network of immune-neuroendocrine interactions[J]. Clin Exp Immunol, 1977, 27(1): 1-12.
[7] Chu C, Artis D, Chiu IM. Neuro-immune interactions in the tissues[J]. Immunity, 2020, 52(3): 464-474.
[8] Akinyemi DE, Chevre R, Soehnlein O. Neuro-immune crosstalk in hematopoiesis, inflammation, and repair[J]. Trends Immunol, 2024, 45(8): 597-608.
[9] Kizil B, De Virgiliis F, Scheiermann C. Neural control of tumor immunity[J]. FEBS J, 2024, 291(21): 4670-4679.
[10] Proctor GB, Shaalan AM. Disease-induced changes in salivary gland function and the composition of saliva[J]. J Dent Res, 2021, 100(11): 1201-1209.
[11] Wang J, Yang ZH, Liu YY, et al. The GAL/GALR2 axis promotes the perineural invasion of salivary a-denoid cystic carcinoma via epithelial-to-mesenchymal transition[J]. Cancer Med, 2023, 12(4): 4496-4509.
[12] Hondermarck H, Jiang CC. Time to introduce nerve density in cancer histopathologic assessment[J]. Clin Cancer Res, 2023, 29(13): 2342-2344.
[13] Reavis HD, Chen HI, Drapkin R. Tumor innervation: cancer has some nerve[J]. Trends Cancer, 2020, 6(12): 1059-1067.
[14] An PG, Wu WJ, Tang YF, et al. Single-cell RNA sequencing reveals the heterogeneity and microenvironment in one adenoid cystic carcinoma sample[J]. Funct Integr Genomics, 2023, 23(2): 155.
[15] Linxweiler M, Kuo FS, Katabi N, et al. The immune microenvironment and neoantigen landscape of aggressive salivary gland carcinomas differ by subtype[J]. Clin Cancer Res, 2020, 26(12): 2859-2870.
[16] Mosconi C, de Arruda JAA, de Farias ACR, et al. Immune microenvironment and evasion mechani-sms in adenoid cystic carcinomas of salivary glands[J]. Oral Oncol, 2019, 88: 95-101.
[17] Lin QQ, Fang ZJ, Sun JL, et al. Single-cell transcriptomic analysis of the tumor ecosystem of adenoid cystic carcinoma[J]. Front Oncol, 2022, 12: 1063477.
[18] Wu Q, Liu Z, Li B, et al. Immunoregulation in cancer-associated cachexia[J]. J Adv Res, 2024, 58: 45-62.
[19] Xu Q, Cao Y, Kong FN, et al. Multiple cancer cell types release LIF and Gal3 to hijack neural signals[J]. Cell Res, 2024, 34(5): 345-354.
[20] Xu YL, Yan JX, Tao Y, et al. Pituitary hormone α- MSH promotes tumor-induced myelopoiesis and immunosuppression[J]. Science, 2022, 377(6610): 1085-1091.
[21] Thiel V, Renders S, Panten J, et al. Characterization of single neurons reprogrammed by pancreatic cancer[J]. Nature, 2025, 640(8060): 1042-1051.
[22] Hörner SJ, Couturier N, Gueiber DC, et al. Development and in vitro differentiation of Schwann cells[J]. Cells, 2022, 11(23): 3753.
[23] Shurin GV, Vats K, Kruglov O, et al. Tumor-induced T cell polarization by Schwann cells[J]. Cells, 2022, 11(22): 3541.
[24] Sun LQ, Chen SH, Chen MY. Schwann cells in the tumor microenvironment: need more attention[J]. J Oncol, 2022: 1058667.
[25] Deborde S, Wong RJ. The role of schwann cells in cancer[J]. Adv Biol, 2022, 6(9): 2200089.
[26] Sun CC, Ye YQ, Tan Z, et al. Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promo-tes pancreatic cancer kynurenine pathway and tumor immune exclusion[J]. Sci Adv, 2023, 9(5): eadd6995.
[27] Huang T, Fan Q, Wang YW, et al. Schwann cell-derived CCL2 promotes the perineural invasion of cervical cancer[J]. Front Oncol, 2020, 10: 19.
[28] Shurin GV, Kruglov O, Ding F, et al. Melanoma-induced reprogramming of Schwann cell signaling aids tumor growth[J]. Cancer Res, 2019, 79(10): 2736-2747.
[29] Martyn GV, Shurin GV, Keskinov AA, et al. Sch-wann cells shape the neuro-immune environs and control cancer progression[J]. Cancer Immunol Immunother, 2019, 68(11): 1819-1829.
[30] Shan C, Wei JH, Hou R, et al. Schwann cells promote EMT and the Schwann-like differentiation of salivary adenoid cystic carcinoma cells via the BD-NF/TrkB axis[J]. Oncol Rep, 2016, 35(1): 427-435.
[31] Chen W, Dong SZ, Zhou J, et al. Investigation of myoepithelial cell differentiation into Schwann-like cells in salivary adenoid cystic carcinoma associa-ted with perineural invasion[J]. Mol Med Rep, 2012, 6(4): 755-759.
[32] Li JJ, Wu CZ, Huang NW, et al. Cancer cell-derived exosomal miRNA induces and reprograms Schwann cells to augment the perineural invasion of salivary adenoid cystic carcinoma[J]. Chin Med J, 2024, 137(20): 2498-2500.
[33] Zhang M, Zheng M, Dai L, et al. CXCL12/CXCR4 facilitates perineural invasion via induction of the Twist/S100A4 axis in salivary adenoid cystic carcinoma[J]. J Cell Mol Med, 2021, 25(16): 7901-7912.
[34] Jin R, Neufeld L, McGaha TL. Linking macrophage metabolism to function in the tumor microenvironment[J]. Nat Cancer, 2025, 6(2): 239-252.
[35] Michaelides I, Künzel J, Ettl T, et al. Adenoid cystic carcinoma of the salivary glands: a pilot study of potential therapeutic targets and characterization of the immunological tumor environment and angiogenesis[J]. Eur Arch Otorhinolaryngol, 2023, 280(6): 2937-2944.
[36] Grover P, McGrath JE, Xiu J, et al. Comprehensive genomic profiling and immune characterization of adenoid cystic carcinoma[J]. J Clin Oncol, 2021, 39(): e18050.
[37] Yang ZH, Li H, Wang WQ, et al. CCL2/CCR2 axis promotes the progression of salivary adenoid cystic carcinoma via recruiting and reprogramming the tumor-associated macrophages[J]. Front Oncol, 2019, 9: 231.
[38] Zhang B, Guo XF, Huang LY, et al. Tumour-associated macrophages and Schwann cells promote perineural invasion via paracrine loop in pancreatic ductal adenocarcinoma[J]. Br J Cancer, 2024, 130(4): 542-554.
[39] Zhou Y, Li JW, Han BH, et al. Schwann cells promote lung cancer proliferation by promoting the M2 polarization of macrophages[J]. Cell Immunol, 2020, 357: 104211.
[40] Liao T, Chen X, Qiu F, et al. Regulation of cancer-associated fibroblasts for enhanced cancer immunotherapy using advanced functional nanomedicines: an updated review[J]. J Nanobiotechnol, 2025, 23(1): 166.
[41] Hu DD, Li ZQ, Zheng B, et al. Cancer-associated fibroblasts in breast cancer: challenges and opportunities[J]. Cancer Commun, 2022, 42(5): 401-434.
[42] Mahdavi N, Aminishakib P, Zavarei M, et al. Adenoid cystic carcinoma and polymorphus adenocarcinoma: an immunohistochemical comparison[J]. Iran J Sci Technol Trans Sci, 2021, 45(6): 1895-1904.
[43] Al-Raimi HAI, Kong J, Ran Y, et al. Extracellular vesicles from carcinoma-associated fibroblasts promote EMT of salivary adenoid cystic carcinoma via IL-6[J]. Arch Med Res, 2023, 54(1): 27-36.
[44] Xu ZL, Zheng X, Zheng JM. Tumor‑derived exosomes educate fibroblasts to promote salivary adenoid cystic carcinoma metastasis via NGF‑NTRK1 pathway[J]. Oncol Lett, 2019, 18(4): 4082-4091.
[45] Li J, Jia ZQ, Kong J, et al. Carcinoma-associated fibroblasts lead the invasion of salivary gland adenoid cystic carcinoma cells by creating an invasive track[J]. PLoS One, 2016, 11(3): e0150247.
[46] Zheng SY, Hu CH, Lin Q, et al. Extracellular vesi-cle-packaged PIAT from cancer-associated fibroblasts drives neural remodeling by mediating m5C modification in pancreatic cancer mouse models[J]. Sci Transl Med, 2024, 16(756): eadi0178.
[47] Shen T, Li Y, Wang D, et al. YAP1-TEAD1 media-tes the perineural invasion of prostate cancer cells induced by cancer-associated fibroblasts[J]. Biochim Biophys Acta Mol Basis Dis, 2022, 1868(12): 166540.
[48] Huang Q, Hu B, Zhang P, et al. Neuroscience of cancer: unraveling the complex interplay between the nervous system, the tumor and the tumor immune microenvironment[J]. Mol Cancer, 2025, 24(1): 24.
[49] Aloe L, Chaldakov GN. Homage to Rita Levi-Montalcini, the queen of modern neuroscience[J]. Cell Biol Int, 2013, 37(8): 761-765.
[50] Li H, Nong XL, Chen Q, et al. Nerve growth factor and vascular endothelial growth factor: retrospective analysis of 63 patients with salivary adenoid cystic carcinoma[J]. Int J Oral Sci, 2010, 2(1): 35-44.
[51] Wang L, Sun MY, Jiang YG, et al. Nerve growth factor and tyrosine kinase A in human salivary adenoid cystic carcinoma: expression patterns and effects on in vitro invasive behavior[J]. J Oral Maxillofac Surg, 2006, 64(4): 636-641.
[52] Benzaquen D, Lawrence YR, Taussky D, et al. The crosstalk between nerves and cancer: a poorly understood phenomenon and new possibilities[J]. Cancers, 2024, 16(10): 1875.
[53] Wang X, Yang TW, Shi SH, et al. Heterogeneity-induced NGF-NGFR communication inefficiency promotes mitotic spindle disorganization in exhausted T cells through PREX1 suppression to impair the anti-tumor immunotherapy with PD-1 mAb in hepatocellular carcinoma[J]. Cancer Med, 2024, 13(3): e6736.
[54] Yin T, Wang GP, Wang LY, et al. Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection[J]. Nat Immunol, 2024, 25(2): 268-281.
[55] Chow R, Wessels JM, Foster WG. Brain-derived neurotrophic factor (BDNF) expression and function in the mammalian reproductive Tract[J]. Hum Reprod Update, 2020, 26(4): 545-564.
[56] Kowalski PJ, Paulino AFG. Perineural invasion in adenoid cystic carcinoma: its causation/promotion by brain-derived neurotrophic factor[J]. Hum Pa-thol, 2002, 33(9): 933-936.
[57] Jia S, Wang WX, Hu ZQ, et al. BDNF mediated TrkB activation contributes to the EMT progression and the poor prognosis in human salivary adenoid cystic carcinoma[J]. Oral Oncol, 2015, 51(1): 64-70.
[58] Yu Q, Wang YT, Yi GM, et al. BDNF is a prognostic biomarker involved in immune infiltration of lung adenocarcinoma and is associated with brain metastasis[J]. Immunology, 2023, 168(2): 320-330.
[59] Boshuizen J, Vredevoogd DW, Krijgsman O, et al. Reversal of pre-existing NGFR-driven tumor and immune therapy resistance[J]. Nat Commun, 2020, 11: 3946.
[60] Ivanov SV, Panaccione A, Brown B, et al. TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior[J]. Oncogene, 2013, 32(32): 3698-3710.
[61] Li H, Yang ZH, Wang WQ, et al. NT-3/TrkC axis contributes to the perineural invasion and the poor prognosis in human salivary adenoid cystic carcinoma[J]. J Cancer, 2019, 10(24): 6065-6073.
[62] Mempel TR, Lill JK, Altenburger LM. How chemokines organize the tumour microenvironment[J]. Nat Rev Cancer, 2024, 24(1): 28-50.
[63] 张艳宁, 石宏, 李荷香, 等. SDC4在唾液腺腺样囊性癌神经侵袭中的作用研究[J]. 口腔医学研究, 2023, 39(12): 1085-1091.
Zhang YN, Shi H, Li HX, et al. Role of SDC4 in perineural invasion of salivary adenoid cystic carcinoma[J]. J Oral Sci Res, 2023, 39(12): 1085-1091.
[64] 马晓周, 刘麒麟, 尹唯凰, 等. CC趋化因子受体6在人唾液腺腺样囊性癌组织中的表达及其临床意义[J]. 吉林大学学报(医学版), 2018, 44(1): 153-156, 214.
Ma XZ, Liu QL, Yin WH, et al. Expression of CCR6 in adenoid cystic carcinoma tissue of salivary glands and its clinical significance[J]. J Jilin Univ (Med Ed), 2018, 44(1): 153-156, 214.
[65] 申志远. 趋化因子CCL5及其受体CCR5在唾液腺腺样囊性癌嗜神经侵袭中的作用和意义[D]. 西安: 第四军医大学, 2013.
Shen ZY. Important role of CCL5/CCR5 axis in perineural invasion of human salivary adenoid cystic carcinoma[D]. Xi'an: The Fourth Military Medical University, 2013.
[66] 孟志兵, 徐晓刚, 周中华. CXCL12/CXCR4在涎腺腺样囊性癌及周围神经组织中的表达[J]. 第二军医大学学报, 2008, 29(6): 639-642.
Meng ZB, Xu XG, Zhou ZH. Expression of CXCL12 and CXCR4 in salivary adenoid cystic carcinoma and peripheral nerve tissues[J]. Acad J Se-cond Mil Med Univ, 2008, 29(6): 639-642.
[67] Yang Z, Li H, Wang J, et al. CCL2/CCR2 axis promotes perineural invasion of salivary adenoid cystic carcinoma via ITGβ5-mediated nerve-tumor interaction[J]. Biochim Biophys Acta Mol Basis Dis, 2025, 1871(1): 167484.
[68] Gao T, Shen ZY, Ma C, et al. The CCL5/CCR5 chemotactic pathway promotes perineural invasion in salivary adenoid cystic carcinoma[J]. J Oral Maxillofac Surg, 2018, 76(8): 1708-1718.
[69] 杜贵霞, 张凡, 刘博, 等. NGF、NCAM、CXCL12/CXCR4在涎腺腺样囊性癌嗜神经侵袭中作用的研究[J]. 神经药理学报, 2015, 5(6): 6-10.
Du GX, Zhang F, Liu B, et al. The study on the role of NGF, NCAM, CXCL12/CXCR4 in salivary adenoid cystic carcinoma perineural invasion[J]. Acta Neuropharmacol, 2015, 5(6): 6-10.
[70] Winkler F, Venkatesh HS, Amit M, et al. Cancer neuroscience: state of the field, emerging directions[J]. Cell, 2023, 186(8): 1689-1707.
[71] Yaniv D, Mattson B, Talbot S, et al. Targeting the peripheral neural-tumour microenvironment for cancer therapy[J]. Nat Rev Drug Discov, 2024, 23(10): 780-796.
[72] Hu T, Yu ZY, Zhao J, et al. Transport and inhibition mechanisms of the human noradrenaline transporter[J]. Nature, 2024, 632(8026): 930-937.
[73] Dantzer R. Neuroimmune interactions: from the brain to the immune system and vice versa[J]. Phy-siol Rev, 2018, 98(1): 477-504.
[74] Ma C, Gao T, Ju J, et al. Sympathetic innervation contributes to perineural invasion of salivary adenoid cystic carcinoma via the β2-adrenergic receptor[J]. Onco Targets Ther, 2019, 12: 1475-1495.
[75] Farooq MA, Ajmal I, Hui XH, et al. β2-adrenergic receptor mediated inhibition of T cell function and its implications for Car-T cell therapy[J]. Int J Mol Sci, 2023, 24(16): 12837.
[76] Zhang Y, Lin CZ, Liu ZQ, et al. Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies[J]. Cell Metab, 2022, 34(12): 1999-2017.e10.
[77] Dai CB, Zhang B, Liao YY, et al. CALCB rs38292-22 T/T genotype and low expression of CALCB are high-risk factors for adenoid cystic carcinoma of sa-livary gland[J]. Dis Markers, 2021: 5546858.
[78] Balood M, Ahmadi M, Eichwald T, et al. Nociceptor neurons affect cancer immunosurveillance[J]. Nature, 2022, 611(7935): 405-412.
[79] Hou YT, Lin B, Xu TY, et al. The neurotransmitter calcitonin gene-related peptide shapes an immunosuppressive microenvironment in medullary thyroid cancer[J]. Nat Commun, 2024, 15: 5555.
[80] Oliveira Volpe CM, Vaz T, Rocha-Silva F, et al. Is galanin a promising therapeutic resource for neural and nonneural diseases[J]. Curr Drug Targets, 2020, 21(9): 922-929.
[81] de Medeiros MC, Liu M, Banerjee R, et al. Gala-nin mediates tumor-induced immunosuppression in head and neck squamous cell carcinoma[J]. Cell Oncol, 2022, 45(2): 241-256.
[82] Zheng YY, Li LF, Shen ZB, et al. Mechanisms of neural infiltration-mediated tumor metabolic reprogramming impacting immunotherapy efficacy in non-small cell lung cancer[J]. J Exp Clin Cancer Res, 2024, 43(1): 284.
[83] Globig AM, Zhao S, Roginsky J, et al. The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion[J]. Nature, 2023, 622(7982): 383-392.
[84] Geng QS, Li LF, Shen ZB, et al. Norepinephrine inhibits CD8+ T-cell infiltration and function, indu-cing anti-PD-1 MAb resistance in lung adenocarcinoma[J]. Br J Cancer, 2023, 128(7): 1223-1235.
[85] Huang D, Wang Y, Thompson JW, et al. Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression[J]. Nat Cell Biol, 2022, 24(2): 230-241.
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