Research progress on the CD300 family and its mechanism of regulating the anti-tumor effects of immune cells

doi:10.3760/cma.j.cn371439-20251106-00048

Abstract

Abstract:

As an important member of the immunoglobulin （Ig） superfamily， the CD300 family possesses conserved Ig domains and diverse intracellular signaling motifs， and is widely present in various immune cells and tumor cells. Due to differences in the structural composition of different subtypes， members of this family are classified into inhibitory or activating receptors， exhibiting functional heterogeneity. They play a dual role in the tumor immune microenvironment： they can either promote immune activation or mediate immune suppression. By directly or indirectly regulating the functions of myeloid cells （macrophages， dendritic cells， polymorphonuclear-like myeloid-derived suppressor cells） and lymphocytes （natural killer cells， T cells） in the tumor immune microenvironment， the CD300 family serves as a key node in tumor immune escape. Based on the anti-tumor effect of CD300 family regulating immune cells， this article reviews the biological functions of CD300 family and its correlation with tumor occurrence and development， which can provide new research ideas for tumor immunotherapy and drug resistance.

Key words: Immunoglobulins, Neoplasms, Tumor microenvironment, CD300 family

Yu Xinjing, Yang Yang, Li Shuyao, Qiao Xiaojuan. Research progress on the CD300 family and its mechanism of regulating the anti-tumor effects of immune cells[J]. Journal of International Oncology, 2026, 53(5): 296-300.

References 45

[1]	Borrego F. The CD300 molecules: an emerging family of regulators of the immune system[J]. Blood, 2013, 121(11): 1951-1960. DOI: 10.1182/blood-2012-09-435057. pmid: 23293083
[2]	Valiate BVS, Alvarez RU, Karra L, et al. The immunoreceptor CD300a controls the intensity of inflammation and dysfunction in a model of Ag-induced arthritis in mice[J]. J Leukoc Biol, 2019, 106(4): 957-966. DOI: 10.1002/JLB.3A1018-389R.
[3]	Munitz A, Bachelet I, Eliashar R, et al. The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils[J]. Blood, 2006, 107(5): 1996-2003. DOI: 10.1182/blood-2005-07-2926. pmid: 16254138
[4]	Cantoni C, Bottino C, Augugliaro R, et al. Molecular and functional characterization of IRp60, a member of the immunoglobulin superfamily that functions as an inhibitory receptor in human NK cells[J]. Eur J Immunol, 1999, 29(10): 3148-3159. DOI: 10.1002/(SICI)1521-4141(199910)29:10<3148::AID-IMMU3148>3.0.CO;2-L.
[5]	Vitallé J, Terrén I, Orrantia A, et al. CD300 receptor family in viral infections[J]. Eur J Immunol, 2019, 49(3): 364-374. DOI: 10.1002/eji.201847951. pmid: 30485414
[6]	Niizuma K, Tahara-Hanaoka S, Noguchi E, et al. Identification and characterization of CD300H, a new member of the human CD300 immunoreceptor family[J]. J Biol Chem, 2015, 290(36): 22298-22308. DOI: 10.1074/jbc.M115.643361. pmid: 26221034
[7]	Lee SI, Kim H, Lim CK, et al. Engagement of CD300c by a novel monoclonal antibody induces the differentiation of monocytes to M1 macrophages[J]. Immunobiology, 2024, 229(1): 152780. DOI: 10.1016/j.imbio.2023.152780.
[8]	Vitallé J, Terrén I, Orrantia A, et al. The Expression and function of CD300 molecules in the main players of allergic responses: mast cells, basophils and eosinophils[J]. Int J Mol Sci, 2020, 21(9): 3173. DOI: 10.3390/ijms21093173.
[9]	Zenarruzabeitia O, Astarloa-Pando G, Terrén I, et al. T cell activation, highly armed cytotoxic cells and a shift in monocytes cd300 receptors expression is characteristic of patients with severe COVID-19[J]. Front Immunol, 2021, 12: 655934. DOI: 10.3389/fimmu.2021.655934.
[10]	Evans F, Alí-Ruiz D, Rego N, et al. CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline[J]. Cell Rep, 2023, 42(10): 113269. DOI: 10.1016/j.celrep.2023.113269.
[11]	Zelenka L, Jarek M, Pägelow D, et al. Crosstalk of highly purified microglia and astrocytes in the frame of toll-like receptor (TLR)2/1 activation[J]. Neuroscience, 2023, 526: 256-266. DOI: 10.1016/j.neuroscience.2023.05.001.
[12]	Lindblad C, Klang A, Bark D, et al. Influence of apolipoprotein E genotype on the proteomic profile in cerebral microdialysis after human severe traumatic brain injury: a prospective observational study[J]. Brain Commun, 2025, 7(2): fcaf096. DOI: 10.1093/braincomms/fcaf096.
[13]	Nakahashi-Oda C, Tahara-Hanaoka S, Shoji M, et al. Apoptotic cells suppress mast cell inflammatory responses via the CD300a immunoreceptor[J]. J Exp Med, 2012, 209(8): 1493-1503. DOI: 10.1084/jem.20120096.
[14]	Dimitrova M, Zenarruzabeitia O, Borrego F, et al. CD300c is uniquely expressed on CD56 bright natural killer cells and differs from CD300a upon ligand recognition[J]. Sci Rep, 2016, 6: 23942. DOI: 10.1038/srep23942. pmid: 27040328
[15]	Lee H, Nakahashi-Oda C, Lyu W, et al. Inhibitory immunoreceptors CD300a and CD300lf cooperate to regulate mast cell activation[J]. J Immunol, 2025, 214(3): 325-334. DOI: 10.1093/jimmun/vkae030. pmid: 40073110
[16]	Yang T, Zhang Y, Duan CJ, et al. CD300E⁺ macrophages facilitate liver regeneration after splenectomy in decompensated cirrhotic patients[J]. Exp Mol Med, 2025, 57(1): 72-85. DOI: 10.1038/s12276-024-01371-3. pmid: 39741181
[17]	Dias C, Levi-Schaffer F, Esteves PJ. Evolutionary analysis of CD300A and CD300C paired receptors in primates[J]. Front Immunol, 2025, 16: 1633323. DOI: 10.3389/fimmu.2025.1633323.
[18]	Negro-Demontel L, Evans F, Cawen FA, et al. CD300f enables microglial damage sensing, efferocytosis, and apoptotic cell metabolization after brain injury[J]. Brain Behav Immun, 2025, 130: 106105. DOI: 10.1016/j.bbi.2025.106105.
[19]	Tamene W, Abebe M, Wassie L, et al. PDL1 expression on monocytes is associated with plasma cytokines in Tuberculosis and HIV[J]. PLoS One, 2021, 16(10): e0258122. DOI: 10.1371/journal.pone.0258122.
[20]	Kavianpour AA, Ghasempour S, Meyer KJ, et al. Phosphatidylethanolamine is a phagocytic ligand implicated in the binding and removal of apoptotic and bacterial extracellular vesicles[J]. Curr Biol, 2025, 35(17): 4276-4284.e5. DOI: 10.1016/j.cub.2025.07.043.
[21]	Wang CX, Zheng XC, Zhang JL, et al. CD300ld on neutrophils is required for tumour-driven immune suppression[J]. Nature, 2023, 621(7980): 830-839. DOI: 10.1038/s41586-023-06511-9.
[22]	Wen XM, Xu ZJ, Ma JC, et al. Bioinformatic characterization of STING expression in hematological malignancies reveals association with prognosis and anti-tumor immunity[J]. Front Immunol, 2025, 16: 1477100. DOI: 10.3389/fimmu.2025.1477100.
[23]	Kawai T, Ikegawa M, Ori D, et al. Decoding Toll-like receptors: recent insights and perspectives in innate immunity[J]. Immunity, 2024, 57(4): 649-673. DOI: 10.1016/j.immuni.2024.03.004. pmid: 38599164
[24]	Demaria O, Cornen S, Daëron M, et al. Harnessing innate immunity in cancer therapy[J]. Nature, 2019, 574(7776): 45-56. DOI: 10.1038/s41586-019-1593-5.
[25]	Rothlin CV, Ghosh S. Lifting the innate immune barriers to antitumor immunity[J]. J Immunother Cancer, 2020, 8(1): e000695. DOI: 10.1136/jitc-2020-000695.
[26]	Yao J, Ji LL, Wang G, et al. Effect of neutrophils on tumor immunity and immunotherapy resistance with underlying mechanisms[J]. Cancer Commun (Lond), 2025, 45(1): 15-42. DOI: 10.1002/cac2.12613.
[27]	Peng JM, Liu HY. CD300a: an innate immune checkpoint shaping tumor immunity and therapeutic opportunity[J]. Cancers (Basel), 2025, 17(11): 1786. DOI: 10.3390/cancers17111786.
[28]	Tian L, Choi SC, Lee HN, et al. Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to auto-immune disease in CD300f-deficient mice[J]. Cell Death Differ, 2016, 23(6): 1086-1096. DOI: 10.1038/cdd.2015.161. pmid: 26768664
[29]	Murakami Y, Tian L, Voss OH, et al. CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition[J]. Cell Death Differ, 2014, 21(11): 1746-1757. DOI: 10.1038/cdd.2014.86. pmid: 25034781
[30]	Voss OH, Tian LJ, Murakami Y, et al. Emerging role of CD300 receptors in regulating myeloid cell efferocytosis[J]. Mol Cell Oncol, 2015, 2(4): e964625. DOI: 10.4161/23723548.2014.964625.
[31]	Nakahashi-Oda C, Udayanga KG, Nakamura Y, et al. Apoptotic epithelial cells control the abundance of treg cells at barrier surfaces[J]. Nat Immunol, 2016, 17(4): 441-450. DOI: 10.1038/ni.3345. pmid: 26855029
[32]	Voss OH, Murakami Y, Pena MY, et al. Lipopolysaccharide-induced CD300b receptor binding to Toll-like receptor 4 alters signaling to drive cytokine responses that enhance septic shock[J]. Immunity, 2016, 44(6): 1365-1378. DOI: 10.1016/j.immuni.2016.05.005. pmid: 27261276
[33]	Moshkovits I, Karo-Atar D, Itan M, et al. CD300f associates with IL-4 receptor α and amplifies IL-4-induced immune cell responses[J]. Proc Natl Acad Sci U S A, 2015, 112(28): 8708-8713. DOI: 10.1073/pnas.1507625112.
[34]	Carroll SL, Pasare C, Barton GM. Control of adaptive immunity by pattern recognition receptors[J]. Immunity, 2024, 57(4): 632-648. DOI: 10.1016/j.immuni.2024.03.014. pmid: 38599163
[35]	Zhang SQ, Thomas F, Fang J, et al. Universal protection of allogeneic T-cell therapies from natural killer cells via CD300a agonism[J]. Blood Adv, 2025, 9(2): 254-264. DOI: 10.1182/bloodadvances.2024013436.
[36]	Kim EJ, Lee SM, Suk K, et al. CD300a and CD300f differentially regulate the MyD88 and TRIF-mediated TLR signalling pathways through activation of SHP-1 and/or SHP-2 in human monocytic cell lines[J]. Immunology, 2012, 135(3): 226-235. DOI: 10.1111/j.1365-2567.2011.03528.x.
[37]	Sutherland SIM, Ju XS, Silveira PA, et al. CD300f signalling induces inhibitory human monocytes/macrophages[J]. Cell Immunol, 2023, 390: 104731. DOI: 10.1016/j.cellimm.2023.104731.
[38]	Simhadri VR, Mariano JL, Gil-Krzewska A, et al. CD300c is an activating receptor expressed on human monocytes[J]. J Innate Immun, 2013, 5(4): 389-400. DOI: 10.1159/000350523. pmid: 23571507
[39]	Coletta S, Salvi V, Della Bella C, et al. The immune receptor CD300e negatively regulates T cell activation by impairing the STAT1-dependent antigen presentation[J]. Sci Rep, 2020, 10(1): 16501. DOI: 10.1038/s41598-020-73552-9. pmid: 33020563
[40]	Silva R, Moir S, Kardava L, et al. CD300a is expressed on human B cells, modulates BCR-mediated signaling, and its expression is down-regulated in HIV infection[J]. Blood, 2011, 117(22): 5870-5880. DOI: 10.1182/blood-2010-09-310318. pmid: 21482706
[41]	Nakano-Yokomizo T, Tahara-Hanaoka S, Nakahashi-Oda C, et al. The immunoreceptor adapter protein DAP12 suppresses B lymphocyte- driven adaptive immune responses[J]. J Exp Med, 2011, 208(8): 1661-1671. DOI: 10.1084/jem.20101623.
[42]	Du XR, Liu B, Ding Q, et al. CD300A inhibits tumor cell growth by downregulating AKT phosphorylation in human glioblastoma multiforme[J]. Int J Clin Exp Pathol, 2018, 11(7): 3471-3478.
[43]	Sun XG, Huang SH, Wang X, et al. CD300A promotes tumor progression by PECAM1, ADCY7 and AKT pathway in acute myeloid leukemia[J]. Oncotarget, 2018, 9(44): 27574-27584. DOI: 10.18632/oncotarget.24164. pmid: 29938007
[44]	Liu N, Sun WC, Gao WX, et al. CD300e: Emerging role and mechanism as an immune-activating receptor[J]. Int Immunopharmacol, 2024, 133: 112055. DOI: 10.1016/j.intimp.2024.112055.
[45]	Abe F, Nakahashi-Oda C, Lee H, et al. A humanized monoclonal antibody against CD300A ameliorates acute ischemic stroke in humanized mice[J]. Monoclon Antib Immunodiagn Immunother, 2025, 44(1): 2-7. DOI: 10.1089/mab.2024.0027. pmid: 39804190