卵巢癌肿瘤微环境相关研究进展

doi:10.12280/gjfckx.20251378

摘要/Abstract

摘要：

肿瘤微环境（tumor microenvironment，TME）作为卵巢癌发生、进展及复发耐药的核心调控因素，其细胞组分、细胞因子网络、代谢状态及免疫功能在肿瘤细胞减灭术与化疗过程中发生显著的动态变化，而这种动态性尚未在临床治疗中得到充分重视。治疗前基线TME呈免疫抑制、基质活化及代谢异常特征，M2型巨噬细胞与调节性T细胞富集，CD8+T细胞功能受损，肿瘤相关成纤维细胞（cancer-associated fibroblast，CAF）持续激活并重塑细胞外基质，同时存在缺氧、高乳酸等代谢紊乱，腹水微环境中富集免疫抑制因子。手术可在短期内降低肿瘤负荷、激活CD8+T细胞，但创伤应激会长期诱导炎症与免疫抑制。短期化疗通过诱导免疫原性细胞死亡激活抗瘤免疫、促进免疫“热化”，长期化疗则导致CAF活化、程序性死亡受体配体1上调，使TME重归抑制态。TME动态演变与预后密切相关，术后早期促炎、中期免疫抑制回升，化疗后免疫状态从“热”转“冷”，均加剧复发耐药。基于TME的靶向治疗策略的研发可能为优化卵巢癌精准治疗开辟新路径。

关键词: 卵巢肿瘤, 癌, 肿瘤微环境, 肿瘤细胞减灭术, 药物疗法，联合, 免疫耐受, 抗药性，肿瘤

Abstract:

The tumor microenvironment (TME) is a pivotal regulator in the initiation, progression, recurrence, and chemoresistance of ovarian cancer. Its cellular constituents, cytokine networks, metabolic status, and immune functions undergo profound dynamic alterations during cytoreductive surgery and chemotherapy, this dynamics have not been adequately considered in clinical practice. The pretreatment baseline TME is characterized by immune suppression, stromal activation, and metabolic reprogramming. It features an enrichment of M2-type macrophages and regulatory T cells, impaired function of CD8+ T cells, persistent activation of cancer-associated fibroblast (CAF) that remodel the extracellular matrix, as well as metabolic disorders such as hypoxia and lactate accumulation. Immunosuppressive factors are enriched in the ascites microenvironment. While surgery can reduce the tumor burden and transiently activate CD8+ T cells in the short term, surgical trauma and stress induces a long-term inflammatory and immunosuppressive state. Short-term chemotherapy may promote an immunologically "hot" state by inducing immunogenic cell death and stimulating antitumor immunity. However, prolonged chemotherapy leads to CAF activation and upregulation of programmed death-ligand 1, ultimately driving the TME back into an immunosuppressive state. The dynamic evolution of the TME is closely associated with prognosis. A pro-inflammatory state in the early postoperative period followed by a resurgence of immunosuppression in the mid-term, and the immune state shifting from "hot" to "cold" after chemotherapy, all contribute to the aggravation of recurrence and therapeutic resistance. Therefore, developing TME-targeted therapeutic strategies may open new avenues for optimizing precision treatment in ovarian cancer.

Key words: Ovarian neoplasms, Carcinoma, Tumor microenvironment, Cytoreduction surgical procedures, Drug therapy, combination, Immune tolerance, Drug resistance, neoplasm

徐梦婷, 鲁娣, 宋殿荣. 卵巢癌肿瘤微环境相关研究进展[J]. 国际妇产科学杂志, 2026, 53(2): 188-193.

XU Meng-ting, LU Di, SONG Dian-rong. Research Progress in the Tumor Microenvironment of Ovarian Cancer[J]. Journal of International Obstetrics and Gynecology, 2026, 53(2): 188-193.

参考文献 39

[1]	中国抗癌协会妇科肿瘤专业委员会. 卵巢恶性肿瘤诊断与治疗指南(2021年版)[J]. 中国癌症杂志, 2021, 31(6):490-500. doi: 10.19401/j.cnki.1007-3639.2021.06.07.
[2]	Fan Z, Han D, Fan X, et al. Ovarian cancer treatment and natural killer cell-based immunotherapy[J]. Front Immunol, 2023, 14:1308143. doi: 10.3389/fimmu.2023.1308143.
[3]	Li M, Ma Y, Dai T, et al. Advance in therapies targeting tumor-associated macrophages in ovarian cancer[J]. Front Immunol, 2025, 16:1677839. doi: 10.3389/fimmu.2025.1677839.
[4]	林蓉沁, 潘秀颉, 卞丽红. FOXP3在卵巢癌肿瘤微环境中表达与生存预后关系的生物信息分析[J]. 中国组织工程研究, 2025, 29(29):6343-6350. doi: 10.12307/2025.794.
[5]	Wang H, Zhou F, Qin W, et al. Metabolic regulation of myeloid-derived suppressor cells in tumor immune microenvironment: targets and therapeutic strategies[J]. Theranostics, 2025, 15(6):2159-2184. doi: 10.7150/thno.105276. pmid: 39990210
[6]	Xu Y, Sun D, He J, et al. Cancer-associated fibroblasts in ovarian cancer: research progress[J]. Front Oncol, 2025, 15:1504762. doi: 10.3389/fonc.2025.1504762.
[7]	Yang N, Abbaspour A, Considine JM, et al. Fibronectin composition and transglutaminase 2 cross-linking cooperatively regulate ovarian cancer cell adhesion in ECM-mimetic constructs[J]. Acta Biomater, 2025 Sep 18:S1742-7061(25)00691-9. doi: 10.1016/j.actbio.2025.09.025.Epub ahead of print.
[8]	Ulevicius J, Jasukaitiene A, Bartkeviciene A, et al. Preoperative Immune Cell Dysregulation Accompanies Ovarian Cancer Patients into the Postoperative Period[J]. Int J Mol Sci, 2024, 25(13):7087. doi: 10.3390/ijms25137087.
[9]	Gu R, Tan S, Xu Y, et al. CT radiomics prediction of CXCL9 expression and survival in ovarian cancer[J]. J Ovarian Res, 2023, 16(1):180. doi: 10.1186/s13048-023-01248-5. pmid: 37644593
[10]	Long R, Ding T, Siu MKL, et al. Abstract 617: Oncogenic CXCL10 triggers CD8+ T cell exhaustion in ovarian cancer[J]. Cancer Res, 2023, 83(Suppl 7):617. doi: 10.1158/1538-7445.AM2023-617. doi: 10.1158/1538-7445.AM2023-617
[11]	Rahman MA, Jalouli M, Bhajan SK, et al. The Role of Hypoxia-Inducible Factor-1α (HIF-1α) in the Progression of Ovarian Cancer: Perspectives on Female Infertility[J]. Cells, 2025, 14(6):437. doi: 10.3390/cells14060437.
[12]	Tian T, Lu Y, Lin J, et al. CPT1A promotes anoikis resistance in esophageal squamous cell carcinoma via redox homeostasis[J]. Redox Biol, 2022, 58:102544. doi: 10.1016/j.redox.2022.102544.
[13]	孙洁, 杨素芬, 白图门, 等. 卵巢癌患者腹水及外周血CD4⁺CD25⁺调节性T细胞含量及抑制功能的研究[J]. 中国性科学, 2016, 25(2):17-19.
[14]	Luo K, Xu Y, Chen J, et al. Noncoding RNA-Mediated Regulation of Myeloid-Derived Suppressor Cells in Cancer[J]. Cancer Manag Res, 2025, 17:2567-2587. doi: 10.2147/CMAR.S550896.
[15]	Yan H, Wang W, Wang S, et al. Clinical effects of debulking surgery combined with neoadjuvant chemotherapy in treating ovarian cancer and its influence on tumor markers and immune function[J]. Pak J Med Sci, 2024, 40(11):2475-2479. doi: 10.12669/pjms.40.11.9337. pmid: 39634876
[16]	Pasquier J, Vidal F, Hoarau-Véchot J, et al. Surgical peritoneal stress creates a pro-metastatic niche promoting resistance to apoptosis via IL-8[J]. J Transl Med, 2018, 16(1):271. doi: 10.1186/s12967-018-1643-z. pmid: 30285881
[17]	Yang Y, Yin S, Li S, et al. Stanniocalcin 1 in tumor microenvironment promotes metastasis of ovarian cancer[J]. Onco Targets Ther, 2019, 12:2789-2798. doi: 10.2147/OTT.S196150.
[18]	Natarajan S, Foreman KM, Soriano MI, et al. Collagen Remodeling in the Hypoxic Tumor-Mesothelial Niche Promotes Ovarian Cancer Metastasis[J]. Cancer Res, 2019, 79(9):2271-2284. doi: 10.1158/0008-5472.CAN-18-2616. pmid: 30862717
[19]	Spagnol G, Ghisoni E, Morotti M, et al. The Impact of Neoadjuvant Chemotherapy on Ovarian Cancer Tumor Microenvironment: A Systematic Review of the Literature[J]. Int J Mol Sci, 2024, 25(13):7070. doi: 10.3390/ijms25137070.
[20]	Brøchner AC, Mikkelsen S, Hegelund I, et al. The immune response is affected for at least three weeks after extensive surgery for ovarian cancer[J]. Dan Med J, 2016, 63(6):A5243.
[21]	Kovács AR, Pál L, Szűcs S, et al. Monocyták és neutrophil granulocyták fagocitafunkciója ovariumcarcinomában[J]. Orv Hetil, 2018, 159(33):1353-1359. doi: 10.1556/650.2018.31142.
[22]	Mantha S, Sarasohn D, Ma W, et al. Ovarian vein thrombosis after debulking surgery for ovarian cancer: epidemiology and clinical significance[J]. Am J Obstet Gynecol, 2015, 213(2):208.e1-4. doi: 10.1016/j.ajog.2015.02.028.
[23]	Lin Y, Zhou X, Ni Y, et al. Metabolic reprogramming of the tumor immune microenvironment in ovarian cancer: A novel orientation for immunotherapy[J]. Front Immunol, 2022, 13:1030831. doi: 10.3389/fimmu.2022.1030831.
[24]	Arcieri M, Capezzali E, Restaino S, et al. Study of the Role of the Tumor Microenvironment in Ovarian Cancer (MICO): A Prospective Monocentric Trial[J]. Cancer Rep(Hoboken), 2025, 8(6):e70242. doi: 10.1002/cnr2.70242.
[25]	Xiong Z, Huang Y, Cao S, et al. A new strategy for the treatment of advanced ovarian cancer: utilizing nanotechnology to regulate the tumor microenvironment[J]. Front Immunol, 2025, 16:1542326. doi: 10.3389/fimmu.2025.1542326.
[26]	Ponton-Almodovar A, Sanderson S, Rattan R, et al. Ovarian tumor microenvironment contributes to tumor progression and chemoresistance[J]. Cancer Drug Resist, 2024, 7:53. doi: 10.20517/cdr.2024.111.
[27]	Feng B, Wu J, Shen B, et al. Cancer-associated fibroblasts and resistance to anticancer therapies: status, mechanisms, and countermeasures[J]. Cancer Cell Int, 2022, 22(1):166. doi: 10.1186/s12935-022-02599-7. pmid: 35488263
[28]	Bravo Melgar J, Laoui D. Chemotherapy Sparks Tertiary Lymphoid Structures in Metastatic Ovarian Cancer[J]. Clin Cancer Res, 2025, 31(1):10-11. doi: 10.1158/1078-0432.CCR-24-2738.
[29]	Lanickova T, Hensler M, Kasikova L, et al. Chemotherapy Drives Tertiary Lymphoid Structures That Correlate with ICI-Responsive TCF1+CD8+ T Cells in Metastatic Ovarian Cancer[J]. Clin Cancer Res, 2025, 31(1):164-180. doi: 10.1158/1078-0432.CCR-24-1594.
[30]	Elorbany S, Berlato C, Carnevalli LS, et al. Immunotherapy that improves response to chemotherapy in high-grade serous ovarian cancer[J]. Nat Commun, 2024, 15(1):10144. doi: 10.1038/s41467-024-54295-x.
[31]	Mei C, Gong W, Wang X, et al. Anti-angiogenic therapy in ovarian cancer: Current understandings and prospects of precision medicine[J]. Front Pharmacol, 2023, 14:1147717. doi: 10.3389/fphar.2023.1147717.
[32]	Duarte Mendes A, Freitas AR, Vicente R, et al. Adipocyte Microenvironment in Ovarian Cancer: A Critical Contributor?[J]. Int J Mol Sci, 2023, 24(23):16589. doi: 10.3390/ijms242316589.
[33]	Wu H, Prados MC, Vaeth M. Metabolic regulation of T cell exhaustion[J]. Immune Discov, 2025, 1(1):10005. DOI: 10.70322/immune.2025.10005.
[34]	Li H, Zhang Y, Tang H, et al. Clinical effects of IPCH after the surgery for ovarian cancer at the middle or advanced stage and its impacts on tumor markers and immune functions[J]. Pak J Med Sci, 2024, 40(9):1919-1924. doi: 10.12669/pjms.40.9.8720. pmid: 39416607
[35]	He T, Zhang J, Zeng L, et al. Composite score of PD-1⁺ CD8⁺ tumor-infiltrating lymphocytes and CD57⁺ CD8⁺ tumor ascites lymphocytes is associated with prognosis and tumor immune microenvironment of patients with advanced high-grade serous ovarian cancer[J]. Chin J Cancer Res, 2025, 37(1):73-89. doi: 10.21147/j.issn.1000-9604.2025.01.06.
[36]	Wang ZH, Peng WB, Zhang P, et al. Lactate in the tumour microenvironment: From immune modulation to therapy[J]. EBioMedicine, 2021, 73:103627. doi: 10.1016/j.ebiom.2021.103627.
[37]	Alatise KL, Gardner S, Alexander-Bryant A. Mechanisms of Drug Resistance in Ovarian Cancer and Associated Gene Targets[J]. Cancers(Basel), 2022, 14(24):6246. doi: 10.3390/cancers14246246.
[38]	Zhou HH, Chen X, Cai LY, et al. Erastin Reverses ABCB1-Mediated Docetaxel Resistance in Ovarian Cancer[J]. Front Oncol, 2019, 9:1398. doi: 10.3389/fonc.2019.01398.
[39]	Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer[J]. N Engl J Med, 2011, 365(26):2473-2483. doi: 10.1056/NEJMoa1104390.