Advances on endoplasmic reticulum stress in the treatment of female reproductive system and breast malignant tumors

doi:10.3969/j.issn.1674-490X.2026.02.001

Abstract

Abstract: Endoplasmic reticulum stress and the unfolded protein response it induces play a critical bidirectional regulatory role in tumor occurrence, progression, and treatment resistance. This signaling pathway not only remodels the tumor immune microenvironment by regulating immune cell function and immunogenic cell death, but is also gaining attention as an important therapeutic target. Ovarian cancer, cervical cancer, endometrial cancer, and breast cancer have high incidence and mortality rates, and their molecular mechanisms are complex and difficult to treat.Therefore, it is crucial to deeply explore the common and specific pathological mechanisms.This review systematically outlines the complex roles of endoplasmic reticulum stress in the aforementioned tumors, focusing particularly on interactions with the tumor immune microenvironment and advances in related drug development, aiming to provide a theoretical foundation for the development of new anti-tumor strategies.

Key words: endoplasmic reticulum stress, unfolded protein response, gynecologic malignant tumors, breast cancer, tumor immune microenvironment

CLC Number:

R733

BAI Zhiyuan, ZHOU Yue. Advances on endoplasmic reticulum stress in the treatment of female reproductive system and breast malignant tumors[J]. Journal of Hebei Medical College for Continuing Education, 2026, 43(2): 1-11.

References

[1] MARTINELLI F, GARBI A. Change in practice in gynecologic oncology during the COVID-19 pandemic: a social media survey[J]. Int J Gynecol Cancer, 2020, 30(8): 1101-1107. DOI: 10.1136/ijgc-2020-001585.
[2] ZENG H M, ZHENG R S, SUN K X, et al. Cancer survival statistics in China 2019-2021: a multicenter, population-based study[J]. J Natl Cancer Cent, 2024, 4(3): 203-213. DOI: 10.1016/j.jncc.2024.06.005.
[3] ROY A, KUMAR A. ER stress and unfolded protein response in cancer Cachexia[J]. Cancers, 2019, 11(12): 1929. DOI: 10.3390/cancers11121929.
[4] BERNALES S, PAPA F R, WALTER P. Intracellular signaling by the unfolded protein response[J]. Annu Rev Cell Dev Biol, 2006, 22: 487-508. DOI: 10.1146/annurev.cellbio.21.122303.120200.
[5] 吉毅聪,冯卫.内质网应激在肿瘤治疗中的研究进展[J].内蒙古医学杂志, 2023, 55(2): 160-163, 167. DOI: 10.16096/J.cnki.nmgyxzz.2023.55.02.009.
[6] ZHANG M H, WANG Y J, XU S L, et al. Endoplasmic reticulum stress-related ten-biomarker risk classifier for survival evaluation in epithelial ovarian cancer and TRPM2: apotential therapeutic target of ovarian cancer[J]. Int J Mol Sci, 2023, 24(18): 14010. DOI: 10.3390/ijms241814010.
[7] EMMANUELLI A, SALVAGNO C, HWANG S M, et al. High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils[J]. Oncoimmunology, 2024, 13(1): 2411070. DOI: 10.1080/2162402X.2024.2411070.
[8] YING Y Q, ZHANG J Y, REN D, et al. ERP29 regulates the proliferation of endometrial carcinoma via M6A modification[J]. Life Sci, 2024, 354: 122976. DOI: 10.1016/j.lfs.2024.122976.
[9] FAN J M, ZHANG M Y, WU H L, et al. Estrogen promotes endometrial cancer development by modulating ZNF626SLK and RFWD3 gene expression and inducing immune inflammatory changes[J]. Biomedicines, 2025, 13(2): 498. DOI: 10.3390/biomedicines13020498.
[10] MARCINIAK S J, CHAMBERS J E, RON D. Pharmacological targeting of endoplasmic reticulum stress in disease[J]. Nat Rev Drug Discov, 2022, 21(2): 115-140. DOI: 10.1038/s41573-021-00320-3.
[11] CHEN S Y, LI Y J, ZHOU Z M, et al. Macrophage hitchhiking nanomedicine for enhanced β-elemene delivery and tumor therapy[J]. Sci Adv, 2025, 11(21): eadw7191. DOI: 10.1126/sciadv.adw7191.
[12] CHOPRA S, GIOVANELLI P, ALVARADO-VAZQUEZ P A, et al. IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain[J]. Science, 2019, 365(6450): eaau6499. DOI: 10.1126/science.aau6499.
[13] 孔庆铎,王永军.IRE1α-XBP1通路在肿瘤中的研究进展[J/OL].妇产与遗传(电子版), 2021, 11(3): 41-45. DOI: 10.3868/j.issn.2095-1558.2021.03.009.
[14] ROZPEDEK W, PYTEL D, MUCHA B, et al. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress[J]. Curr Mol Med, 2016, 16(6): 533-544. DOI: 10.2174/1566524016666160523143937.
[15] 马炜祥,张婷婷,崔凤针,等.内质网应激关键分子ATF6α在癌症中作用的研究进展[J].华中科技大学学报(医学版), 2022, 51(2): 241-246, 253. DOI: 10.3870/j.issn.1672-0741.2022.02.018.
[16] OLAWAIYE A B, GLADIEFF L, O'MALLEY D M, et al. Relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer(ROSELLA): an open-label, randomised, controlled, phase 3 trial[J]. Lancet, 2025, 405(10496): 2205-2216. DOI: 10.1016/S0140-6736(25)01040-2.
[17] 游丽鑫.抑制IRE1α可增强AZD1775在TP53突变型卵巢癌中的抗肿瘤作用[D].武汉:华中科技大学, 2022: 39-88.
[18] 程美玉.靶向线粒体PHB2/OMA1/DELE1途径增强顺铂诱导卵巢癌细胞凋亡的机制研究[D].长春:吉林大学, 2022: 27-88.
[19] LV S Y, ZHANG L, WU M, et al. IRE1α inhibitor reduces cisplatin resistance in ovarian cancer by modulating IRE1α/XBP1 pathway[J]. Cell Oncol(Dordr), 2024, 47(6): 2233-2246. DOI: 10.1007/s13402-024-01010-z.
[20] MU W T, ZHI Y, ZHOU J P, et al. Endoplasmic reticulum stress and quality control in relation to cisplatin resistance in tumor cells[J]. Front Pharmacol, 2024, 15: 1419468. DOI: 10.3389/fphar.2024.1419468.
[21] VANDER PLOEG P, VAN LIESHOUT L A M, VANDE STOLPE A, et al. Functional estrogen receptor signaling pathway activity in high-grade serous ovarian carcinoma as compared to estrogen receptor protein expression by immunohistochemistry[J]. Cell Oncol(Dordr), 2021, 44(4): 951-957. DOI: 10.1007/s13402-021-00600-5.
[22] BOWTELL D D, BÖHM S, AHMED A A, et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer[J]. Nat Rev Cancer, 2015, 15(11): 668-679. DOI: 10.1038/nrc4019.
[23] HWANG S M, AWASTHI D, JEONG J, et al. Transgelin 2 guards T cell lipid metabolism and antitumour function[J]. Nature, 2024, 635(8040): 1010-1018. DOI: 10.1038/s41586-024-08071-y.
[24] HWANG S M, CHANG S, RODRIGUEZ P C, et al. Endoplasmic reticulum stress responses in anticancer immunity[J].Nat Rev Cancer, 2025,25(9):684-702. DOI: 10.1038/s41568-025-00836-5.
[25] YANG Z L, HUO Y Z, ZHOU S X, et al. Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production[J]. Cell Metab, 2022, 34(12): 2018-2035. DOI: 10.1016/j.cmet.2022.10.010.
[26] GHORBANHOSSEINI S S, NOURBAKHSH M, MOSAFFA F, et al. Targeting the PERK/NRF2 pathway: enhancing cisplatin efficacy in resistant ovarian cancer cells via MRP1 and ROS modulation[J]. Food Chem Toxicol, 2025, 204: 115672. DOI: 10.1016/j.fct.2025.115672.
[27] ZHANG T, WU Y, HU Z T, et al. Small-molecule integrated stress response inhibitor reduces susceptibility to postinfarct atrial fibrillation in rats via the inhibition of integrated stress responses[J]. J Pharmacol Exp Ther, 2021, 378(3): 197-206. DOI: 10.1124/jpet.121.000491.
[28] ZHAO L N, ZENG L D, TAN S, et al. RXRA induces endoplasmic reticulum stress via ATP2A3 transcriptional modulation in ovarian cancer cells[J]. Arch Med Sci, 2025,21(2):1-21. DOI: 10.5114/aoms/199701.
[29] VAN BEEK N, KLIONSKY D J, REGGIORI F. Genetic aberrations in macroautophagy genes leading to diseases[J]. Biochim Biophys Acta Mol Cell Res, 2018, 1865(5): 803-816. DOI: 10.1016/j.bbamcr.2018.03.002.
[30] LIU X, SONG J, LIU H, et al. Endoplasmic reticulum stress could predict the prognosis of cervical cancer and regulate the occurrence of radiation mucositis[J]. Dose Response, 2023, 21(2): 15593258231173199. DOI: 10.1177/15593258231 173199.
[31] 徐冶.顺铂诱导人宫颈癌细胞死亡中内质网—自噬途径调控作用及机制研究[D].长春:吉林大学, 2012: 28-96.
[32] 郭军飞,赖卫明,马从利,等.IRE1a与miR-346相互调节维持内质网应激强度促进宫颈癌细胞顺铂耐药[J].实用医学杂志, 2021, 37(17): 2176-2181. DOI: 10.3969/j.issn.1006-5725.2021.17.002.
[33] MAO M Y, YOU T Z, XU K J, et al. TRIM3 modulates cisplmatin-resistant of cervical squamous cell carcinoma via endoplasmic reticulum stress signaling in vitro[J]. Biochim Biol Cell, 2025, 103: 1-12. DOI: 10.1139/bcb-2024-0154.
[34] CAO G X, WANG Y H, ZENG H M, et al. Oligoclonal tumor-specific CD8 T-cell revival and IRE1α/XBP1-GDF15-mediated immunosuppressive niches determine neoadjuvant chemoimmunotherapy efficacy in cervical cancer[J]. J Immunother Cancer, 2025, 13(11): e012630. DOI: 10.1136/jitc-2025-012630.
[35] FANG K, YUAN S, ZHANG X, et al. Regulation of immunogenic cell death and potential applications in cancer therapy[J]. Front Immunol, 2025, 16: 1571212. DOI: 10.3389/fimmu.2025.1571212.
[36] WU C Y, HUANG C X, LAO X M, et al. Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL[J]. Cell, 2025, 188(20): 5701-5716. DOI: 10.1016/j.cell.2025.06.027.
[37] 高敏,魏丽惠,孙蓬明,等.雌、孕激素对子宫内膜癌细胞孤儿受体ERRα的调控作用[J].北京大学学报(医学版), 2005, 37(3): 281-283. DOI: 10.3321/j.issn:1671-167X.2005.03.014.
[38] ZHENG Z Z, CHEN L, HU G S, et al. Nuclear receptor ESRRA promotes ERα-positive breast cancer through dual action on super enhancers and promoters to regulate gene transcriptional programs[J]. Sci Bull, 2025, 70(22): 3822-3839. DOI: 10.1016/j.scib.2025.09.044.
[39] 王铭洋,范文生,叶明侠,等.子宫内膜癌分子分型及临床应用研究进展[J].现代妇产科进展, 2021, 30(4): 307-310, 313. DOI: 10.13283/j.cnki.xdfckjz.2021.04.033.
[40] WILLVONSEDER B, STÖGBAUER F, STEIGER K, et al. The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: mutual correlations and prognostic impact depending on molecular alterations[J]. Cancer Immunol Immunother, 2021, 70(6): 1679-1689. DOI: 10.1007/s00262-020-02813-3.
[41] LARA M S, RIESS J W, KALEKA G, et al. POLE mutation associated with microsatellite instability and high tumor mutational burden confers exquisite sensitivity to immune checkpoint inhibitor therapy in non-small cell lung cancer: acase report and genomic database analysis[J]. Clin Lung Cancer, 2025, 26(3): e207-e213. DOI: 10.1016/j.cllc.2025.01.005.
[42] URRA H, DUFEY E, AVRIL T, et al. Endoplasmic reticulum stress and the hallmarks of cancer[J]. Trends Cancer, 2016, 2(5): 252-262. DOI: 10.1016/j.trecan.2016.03.007.
[43] DING N, ZHANG T, YU X H, et al. T-box transcription factor 2 enhances chemoresistance of endometrial cancer by mediating NRF2 expression[J]. Curr Protein Pept Sci, 2022, 23(8): 563-570. DOI: 10.2174/138920372366622082315 2239.
[44] ZUNDELL J A, FUKUMOTO T, LIN J H, et al. Targeting the IRE1α/XBP1 endoplasmic reticulum stress response pathway in ARID1A-mutant ovarian cancers[J]. Cancer Res, 2021, 81(20): 5325-5335. DOI: 10.1158/0008-5472.CAN-21-1545.
[45] ZHU S L, QI M, CHEN M T, et al. A novel DDIT3 activator dehydroevodiamine effectively inhibits tumor growth and tumor cell stemness in pancreatic cancer[J]. Phytomedicine, 2024, 128: 155377. DOI: 10.1016/j.phymed.2024.155377.
[46] 陈洁,吕青,王竹,等.乳腺癌分子病理学指标分布的异质性[J].中国普外基础与临床杂志, 2016, 23(6): 761-766. DOI: 10.7507/1007-9424.20160200.
[47] YUAN J, YANG L, LI Z, et al. The role of the tumor microenvironment in endocrine therapy resistance in hormone receptor-positive breast cancer[J]. Front Endocrinol, 2023, 14: 1261283. DOI: 10.3389/fendo.2023.1261283.
[48] BOUDREAU M W, DURAKI D, WANG L, et al. A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice[J]. Sci Transl Med, 2021, 13(603): eabf1383. DOI: 10.1126/scitranslmed.abf1383.
[49] CHEN X, ILIOPOULOS D, ZHANG Q, et al. XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway[J]. Nature, 2014, 508(7494): 103-107. DOI: 10.1038/nature13119.
[50] JIANG D D, GUO Y M, WANG T Y, et al. IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis[J]. Nat Commun, 2024, 15: 4114. DOI: 10.1038/s41467-024-48330-0.
[51] XU L Y, PENG F L, LUO Q, et al. IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer[J]. Cell, 2024, 187(25): 7248-7266. DOI: 10.1016/j.cell.2024.09.032.
[52] DARINI C, GHADDAR N, CHABOT C, et al. An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy[J]. Nat Commun, 2019, 10(1): 2139. DOI: 10.1038/s41467-019-10138-8.
[53] WANG H, YANG X, DENG L Y, et al. ATF6α inhibits ΔNp63α expression to promote breast cancer metastasis by the GRP78-AKT1-FOXO3a signaling[J]. Cell Death Dis, 2025, 16(1): 289. DOI: 10.1038/s41419-025-07619-8.
[54] PALOMEQUE J Á, SERRA-MIR G, BLASCO-BENITO S, et al. Estrogen receptor signaling drives immune evasion and immunotherapy resistance in HR+ breast cancer[J].J Clin Invest, 2026,136(2):e193153. DOI: 10.1172/JCI193153.
[55] 王守莹,杜彦艳,曹鹏,等.NDRG2调控IRE1α-XBP1介导内质网应激逆转ER+乳腺癌他莫昔芬耐药[J].中国生物化学与分子生物学报, 2024, 40(10): 1409-1416. DOI: 10.13865/j.cnki.cjbmb.2024.09.1182.
[56] CUBILLOS-RUIZ J R, BETTIGOLE S E, GLIMCHER L H. Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer[J]. Cell, 2017, 168(4): 692-706. DOI: 10.1016/j.cell.2016.12.004.
[57] LOGUE S E, MCGRATH E P, CLEARY P, et al. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy[J]. Nat Commun, 2018, 9(1): 3267. DOI: 10.1038/s41467-018-05763-8.
[58] MIMURA N, FULCINITI M, GORGUN G, et al. Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma[J]. Blood, 2012, 119(24): 5772-5781. DOI: 10.1182/blood-2011-07-366633.
[59] AXTEN J M, ROMERIL S P, SHU A, et al. Discovery of GSK2656157: an optimized PERK inhibitor selected for preclinical development[J]. ACS Med Chem Lett, 2013, 4(10): 964-968. DOI: 10.1021/ml400228e.
[60] LEE D M, SEO M J, LEE H J, et al. ISRIB plus bortezomib triggers paraptosis in breast cancer cells via enhanced translation and subsequent proteotoxic stress[J]. Biochem Biophys Res Commun, 2022, 596: 56-62. DOI: 10.1016/j.bbrc.2022.01.082.
[61] VARONE E, DECIO A, BARBERA M C, et al. Endoplasmic reticulum oxidoreductin 1-alpha deficiency and activation of protein translation synergistically impair breast tumour resilience[J]. Br J Pharmacol, 2022, 179(23): 5180-5195. DOI: 10.1111/bph.15927.
[62] TANG Y J, CHEN H, YI Y, et al. Inhibition of eIF2α dephosphorylation protects hepatocytes from apoptosis by alleviating ER stress in acute liver injury[J]. Biomed Res Int, 2020, 2020: 2626090. DOI: 10.1155/2020/2626090.
[63] GALLAGHER C M, GARRI C, CAIN E L, et al. Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch[J]. eLife, 2016, 5: e11878. DOI: 10.7554/eLife.11878.
[64] UNAL B, SAATCIOGLU F. Targeting the unfolded protein response for cancer therapy: mitigating tumor adaptation and immune suppression[J]. Biomark Res, 2025, 13(1): 156. DOI: 10.1186/s40364-025-00813-y.
[65] SCHÖNTHAL A H. Pharmacological targeting of endoplasmic reticulum stress signaling in cancer[J]. Biochem Pharmacol, 2013, 85(5): 653-666. DOI: 10.1016/j.bcp.2012.09.012.
[66] JEWER M, LEE L, LEIBOVITCH M, et al. Translational control of breast cancer plasticity[J]. Nat Commun, 2020, 11(1): 2498. DOI: 10.1038/s41467-020-16352-z.
[67] UNAL B, KUZU O F, JIN Y, et al. Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer[J]. Nat Commun, 2024, 15(1): 8895. DOI: 10.1038/s41467-024-53039-1.
[68] SHI R X, WANG M, CHEN S, et al. Manganese suppresses tumor growth through hyper-activating IRE1α[J]. iScience, 2025, 28(8): 113121. DOI: 10.1016/j.isci.2025.113121.
[69] ZHANG Y M, YAN Y, LIU J X, et al. An endoplasmic reticulum stress-specific nanoinducer selectively evokes type-II immunogenic cell death for pyroptotic cancer immunotherapy[J]. Adv Mater, 2025, 37(32): e2501953. DOI: 10.1002/adma.202501953.