Research progress of LSD1 in regulating tumor immune mechanisms

doi:10.16352/j.issn.1001-6325.2025.08.1088

Abstract

Abstract: Lysine-specific demethylase 1(LSD1) plays a regulatory role in tumor immunity. LSD1 affects CD8⁺T cell infiltration by regulating AGO2 protein level, and it is required for normal B cell proliferation and differentiation via reducing local chromatin accessibility. LSD1 inhibition promotes NK cell cytotoxicity of cancer cells through restoring the expression of ULBPs. LSD1 affects the resistance of M1 macrophages to oxidative stress by regulating the level of SOD2; In addition, regulating the expression of LSD1 affects the anti-tumor function of CD19 CAR-T cells and immune checkpoint blockers. The development of drugs targeting LSD1 will provide new ideas for immunotherapy of tumors.

Key words: LSD1, tumor immunity, immunotherapy, tumor microenvironment, immune checkpoint

CLC Number:

R392.1

LONG Lijuan, SONG Songze, YE Qinong, LIN Jing. Research progress of LSD1 in regulating tumor immune mechanisms[J]. Basic & Clinical Medicine, 2025, 45(8): 1088-1092.

References

[1] Lee DY, Salahuddin T, Iqbal J.Lysine-specific demethylase 1 (LSD1)-mediated epigenetic modification of immunogenicity and immunomodulatory effects in breast cancers[J]. Curr Oncol, 2023, 30:2127-2143.
[2] Doi K, Murata K, Ito S, et al. Role of lysine-specific demethylase 1 in metabolically integrating osteoclast differentiation and inflammatory bone resorption through hypoxia-inducible factor 1α and E2F1[J]. Arthritis Rheumatol, 2022, 74:948-960.
[3] Mamun MAA, Zhang Y, Zhao JY, et al. LSD1: an emerging face in altering the tumor microenvironment and enhancing immune checkpoint therapy[J]. J Biomed Sci, 2023, 30:60. doi: 10.1186/s12929-023-00952-0.
[4] Giles JR, Globig AM, Kaech SM, et al. CD8⁺T cells in the cancer-immunity cycle[J]. Immunity, 2023, 56:2231-2253.
[5] Sheng W, Lafleur MW, Nguyen TH, et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade[J]. Cell, 2018, 174:549-563 e19. doi:10.1016/j.cell.2018.05.052.
[6] Liu Y, Debo B, Li M, et al. LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade[J]. Nat Commun, 2021, 12:6831. doi:10.1038/s41467-021-27179-7.
[7] Shen DD, Pang JR, Bi YP, et al. LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer[J]. Mol Cancer, 2022, 21:75. doi:10.1186/s12943-022-01557-1.
[8] Hiatt JB, Sandborg H, Garrison SM, et al. Inhibition of LSD1 with bomedemstat sensitizes small cell lung cancer to immune checkpoint blockade and T-cell killing[J]. Clin Cancer Res, 2022, 28:4551-4564.
[9] Qin Y, Vasilatos SN, Chen L, et al. Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade[J]. Oncogene, 2019, 38:390-405.
[10] Song S, Zhang D, Chen J, et al. CHMP4A stimulates CD8⁺T-lymphocyte infiltration and inhibits breast tumor growth via the LSD1/IFNβ axis[J]. Cancer Sci, 2023, 114:3162-3175.
[11] Bryushkova EA, Mushenkova NV, Turchaninova MA, et al. B cell clonality in cancer[J]. Semin Immunol, 2024, 72:101874. doi:10.1016/j.smim.2024.101874.
[12] Haines RR, Barwick BG, Scharer CD, et al. The histone demethylase LSD1 regulates B cell proliferation and plasmablast differentiation[J]. J Immunol, 2018, 201:2799-2811.
[13] Liu M, Du M, Yu J, et al. CEBPA mutants down-regulate AML cell susceptibility to NK-mediated lysis by disruption of the expression of NKG2D ligands, which can be restored by LSD1 inhibition[J]. Oncoimmunology, 2022, 11:2016158. doi:10.1080/2162402X.2021.2016158.
[14] Bailey CP, Fiueroa M, Gangadharan A, et al. Pharmacologic inhibition of lysine-specific demethylase 1 as a therapeutic and immune-sensitization strategy in pediatric high-grade glioma[J]. Neuro Oncol, 2020, 22:1302-1314.
[15] Boutilier AJ, Elsawa SF. Macrophage polarization states in the tumor microenvironment[J]. Int J Mol Sci, 2021, 22:6995. doi:10.3390/ijms22136995.
[16] Tokarz P, Plosaz T, Regdon Z, et al. PARP1-LSD1 functional interplay controls transcription of SOD2 that protects human pro-inflammatory macrophages from death under an oxidative condition[J]. Free Radic Biol Med, 2019, 131:218-224.
[17] Jogalekar MP, Rajendran RL, Khan F, et al. CAR T-cell-based gene therapy for cancers: new perspectives, challenges, and clinical developments[J]. Front Immunol, 2022, 13:925985. doi:10.3389/fimmu.2022.925985.
[18] González Barca E. Role of bispecific antibodies in relapsed/refractory diffuse large B-Cell lymphoma in the CART Era[J]. Front Immunol, 2022, 13:909008. doi:10.3389/fimmu.2022.909008.
[19] Si Lim SJ, Grupp SA, DiNofia AM. Tisagenlecleucel for treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia[J]. Pediatr Blood Cancer, 2021, 68:e29123. doi:10.1002/pbc.29123.
[20] Zhang J, Zhu J, Zheng G, et al. Co-expression of miR155 or LSD1 shRNA increases the anti-tumor functions of CD19 CAR-T cells[J]. Front Immunol, 2021, 12:811364. doi:10.3389/fimmu.2021.811364.
[21] Gao M, Shi J, Xiao X, et al. PD-1 regulation in immune homeostasis and immunotherapy[J]. Cancer Lett, 2024, 588:216726. doi:10.1016/j.canlet.2024.216726.
[22] Han Y, Xu S, Ye W, et al. Targeting LSD1 suppresses stem cell-like properties and sensitizes head and neck squamous cell carcinoma to PD-1 blockade[J]. Cell Death Dis, 2021, 12:993. doi:10.1038/s41419-021-04297-0.
[23] Sheng W, Liu Y, Chakraborty D, et al. Simultaneous inhibition of LSD1 and TGFβ enables eradication of poorly immunogenic tumors with anti-PD-1 treatment[J]. Cancer Discov, 2021, 11:1970-1981.
[24] Noce B, Di Bello E, Fioravanti R, et al. LSD1 inhibitors for cancer treatment: focus on multi-target agents and compounds in clinical trials[J]. Front Pharmacol, 2023, 14:1120911. doi:10.3389/fphar.2023.1120911.