Research Advances in the Immune Microenvironment and Immunotherapy for p53-Abnormal Endometrial Carcinoma

doi:10.12280/gjfckx.20251450

Abstract

Abstract:

The p53-abnormal (p53abn) subtype is the molecular subtype with the worst prognosis in endometrial cancer. Its immune microenvironment exhibits significant suppressive features, including functional exhausion of CD8+ T cells, enrichment of regulatory T cells, and polarization toward M2-type macrophages. Although this subtype generally demonstrates low tumor mutational burden and high chromosomal instability, resulting in weak immunogenicity, a subset of cases show high expression of programmed death-ligand 1 (PD-L1) and are enriched in T cells, displaying heterogeneity as 'hot tumors'. In terms of treatment, immune checkpoint inhibitors as monotherapy have limited efficacy. However, multiple phase Ⅲ clinical trials have confirmed that combining immunotherapy with chemotherapy, anti-angiogenic agents, or poly (ADP-ribose) polymerase (PARP) inhibitors can significantly improve patient outcomes, particularly in advanced or recurrent cases. This review summarizes the research progress on the characteristics of the immune microenvironment and immunotherapy strategies for p53abn endometrial cancer, providing theoretical foundations and practical reference for clinical precision subtyping, immunotherapy decision-making, and optimization of combination regimens.

Key words: Genes, p53, Endometrial neoplasms, Carcinoma, Tumor microenvironment, Immune checkpoint inhibitors, Antineoplastic combined chemotherapy protocols

XIANG Xiao-ying, SUN Ya-ge, ZHANG Yun-feng, JIA Han, WANG Yue. Research Advances in the Immune Microenvironment and Immunotherapy for p53-Abnormal Endometrial Carcinoma[J]. Journal of International Obstetrics and Gynecology, 2026, 53(3): 285-291.

References 36

[1]	Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022[J]. J Natl Cancer Cent, 2024, 4(1):47-53. doi: 10.1016/j.jncc.2024.01.006.
[2]	赵湘铃, 段朝晖, 张敏, 等. 中国子宫内膜癌疾病负担状况及流行趋势预测[J]. 中国慢性病预防与控制, 2023, 31(8):568-573. doi: 10.16386/j.cjpccd.issn.1004-6194.2023.08.002.
[3]	Cree IA, White VA, Indave BI, et al. Revising the WHO classification: female genital tract tumours[J]. Histopathology, 2020, 76(1):151-156. doi: 10.1111/his.13977. pmid: 31846528
[4]	Jamieson A, Thompson EF, Huvila J, et al. p53abn Endometrial Cancer: understanding the most aggressive endometrial cancers in the era of molecular classification[J]. Int J Gynecol Cancer, 2021, 31(6):907-913. doi: 10.1136/ijgc-2020-002256. pmid: 33589443
[5]	Berek JS, Matias-Guiu X, Creutzberg C, et al. FIGO staging of endometrial cancer: 2023[J]. Int J Gynaecol Obstet, 2023, 162(2):383-394. doi: 10.1002/ijgo.14923. pmid: 37337978
[6]	Yanaihara N, Tse KY, Lee SJ, et al. Immune checkpoint inhibitors in gynecologic oncology: Current status and perspectives[J]. Int J Gynaecol Obstet, 2025, 171(Suppl 1):166-188. doi: 10.1002/ijgo.70280.
[7]	Li BL, Wan XP. Prognostic significance of immune landscape in tumour microenvironment of endometrial cancer[J]. J Cell Mol Med, 2020, 24(14):7767-7777. doi: 10.1111/jcmm.15408.
[8]	Kumar V. Cytotoxic T Cells: Kill, Memorize, and Mask to Maintain Immune Homeostasis[J]. Int J Mol Sci, 2025, 26(18):8788. doi: 10.3390/ijms26188788.
[9]	Dai Y, Zhao L, Hua D, et al. Tumor immune microenvironment in endometrial cancer of different molecular subtypes: evidence from a retrospective observational study[J]. Front Immunol, 2022, 13:1035616. doi: 10.3389/fimmu.2022.1035616.
[10]	Hattori S, Yoshikawa N, Liu W, et al. Understanding the impact of spatial immunophenotypes on the survival of endometrial cancer patients through the ProMisE classification[J]. Cancer Immunol Immunother, 2025, 74(2):70. doi: 10.1007/s00262-024-03919-8. pmid: 39751650
[11]	Yamagami W, Susumu N, Tanaka H, et al. Immunofluorescence-detected infiltration of CD4+FOXP3+ regulatory T cells is relevant to the prognosis of patients with endometrial cancer[J]. Int J Gynecol Cancer, 2011, 21(9):1628-1634. doi: 10.1097/IGC.0b013e31822c271f. pmid: 21897268
[12]	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. pmid: 33340331
[13]	Degos C, Heinemann M, Barrou J, et al. Endometrial Tumor Microenvironment Alters Human NK Cell Recruitment, and Resident NK Cell Phenotype and Function[J]. Front Immunol, 2019, 10:877. doi: 10.3389/fimmu.2019.00877. pmid: 31105699
[14]	Ren F, Wang L, Wang Y, et al. Single-cell transcriptome profiles the heterogeneity of tumor cells and microenvironments for different pathological endometrial cancer and identifies specific sensitive drugs[J]. Cell Death Dis, 2024, 15(8):571. doi: 10.1038/s41419-024-06960-8. pmid: 39112478
[15]	Sun Y, Jiang G, Wu Q, et al. The role of tumor-associated macrophages in the progression, prognosis and treatment of endometrial cancer[J]. Front Oncol, 2023, 13:1213347. doi: 10.3389/fonc.2023.1213347.
[16]	郭晶晶, 李婷, 王历, 等. 子宫内膜癌分子亚型的免疫浸润特征分析[J]. 实用妇产科杂志, 2025, 41(4):312-318.
[17]	Le Saux O, Sabatier R, Treilleux I, et al. Immune landscape and TAM density in endometrial cancer: implications for immune checkpoint inhibitors efficacy[J]. Ther Adv Med Oncol, 2025, 17:17588359251347364. doi: 10.1177/17588359251347364.
[18]	Zhang Y, Ju B, Cheng R, et al. PD-L1 expression and immune infiltration across molecular subtypes of endometrial cancer: An integrative-analysis of molecular classification and immune subtypes[J]. Hum Pathol, 2024, 154:105704. doi: 10.1016/j.humpath.2024.105704.
[19]	Martin SD, Thornton S, Chow C, et al. Activated immune infiltrates expand opportunities for targeted therapy in p53-abnormal endometrial carcinoma[J]. J Pathol, 2025, 266(3):292-305. doi: 10.1002/path.6429.
[20]	Ahmed MM, Hussein S, Abdalsalam MM, et al. Prognostic implication of CD47 and CTLA-4 expressions in endometrial carcinoma[J]. Hum Immunol, 2025, 86(1):111210. doi: 10.1016/j.humimm.2024.111210.
[21]	Park J, Skålhegg BS. Combination of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of cancer-a brief update[J]. Front Immunol, 2025, 16:1680838. doi: 10.3389/fimmu.2025.1680838.
[22]	Zhang Y, Yang R, Xu C, et al. Analysis of the immune checkpoint lymphocyte activation gene-3 (LAG-3) in endometrial cancer: An emerging target for immunotherapy[J]. Pathol Res Pract, 2022, 236:153990. doi: 10.1016/j.prp.2022.153990.
[23]	Hong JH, Cho HW, Ouh YT, et al. Lymphocyte activation gene (LAG)-3 is a potential immunotherapeutic target for microsatellite stable, programmed death-ligand 1 (PD-L1)-positive endometrioid endometrial cancer[J]. J Gynecol Oncol, 2023, 34(2):e18. doi: 10.3802/jgo.2023.34.e18.
[24]	Lu L, Deng L. TIM-3 inhibitors: a promising strategy for tumor immunotherapy[J]. Trends Mol Med, 2024, 30(3):202-203. doi: 10.1016/j.molmed.2024.01.004. pmid: 38302316
[25]	Chen H, Molberg K, Carrick K, et al. Prevalence and prognostic significance of PD-L1, TIM-3 and B7-H3 expression in endometrial serous carcinoma[J]. Mod Pathol, 2022, 35(12):1955-1965. doi: 10.1038/s41379-022-01131-6.
[26]	Zhang Y, Yang R, Xu C, et al. Risk stratification and molecular heterogeneity of endometrial cancer and expression profile of TIM-3: A retrospective cohort study[J]. Gynecol Oncol, 2023, 170:210-220. doi: 10.1016/j.ygyno.2023.01.024. pmid: 36709662
[27]	Yan Z, Wang C, Wu J, et al. TIM-3 teams up with PD-1 in cancer immunotherapy: mechanisms and perspectives[J]. Mol Biomed, 2025, 6(1):27. doi: 10.1186/s43556-025-00267-6. pmid: 40332725
[28]	Mukherjee O, Rakshit S, Shanmugam G, et al. Role of chemotherapeutic drugs in immunomodulation of cancer[J]. Curr Res Immunol, 2023, 4:100068. doi: 10.1016/j.crimmu.2023.100068.
[29]	Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer: overall survival and exploratory analyses of the NRG GY 018 phase 3 randomized trial[J]. Nat Med, 2025, 31(5):1539-1546. doi: 10.1038/s41591-025-03566-1.
[30]	Powell MA, Bjørge L, Willmott L, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial[J]. Ann Oncol, 2024, 35(8):728-738. doi: 10.1016/j.annonc.2024.05.546. pmid: 38866180
[31]	Van Gorp T, Cibula D, Lv W, et al. ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase Ⅲ study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer[J]. Ann Oncol, 2024, 35(11):968-980. doi: 10.1016/j.annonc.2024.08.2242. pmid: 39284383
[32]	Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase Ⅲ Study 309/KEYNOTE-775[J]. J Clin Oncol, 2023, 41(16):2904-2910. doi: 10.1200/JCO.22.02152.
[33]	Zeng Z, Wei W, Cui L, et al. Overall survival and subsequent therapy from a phase II study of sintilimab and anlotinib in patients with advanced or recurrent endometrial cancer[J]. J Clin Oncol, 2023, 41(Suppl 16):5598. doi: 10.1200/JCO.2023.41.16_suppl.5598.
[34]	Tian W, Ren Y, Lu J, et al. Camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer after failure of at least one prior systemic therapy (CAP 04): a single-arm phase Ⅱ trial[J]. BMC Med, 2024, 22(1):344. doi: 10.1186/s12916-024-03564-z.
[35]	Musacchio L, Caruso G, Pisano C, et al. PARP Inhibitors in Endometrial Cancer: Current Status and Perspectives[J]. Cancer Manag Res, 2020, 12:6123-6135. doi: 10.2147/CMAR.S221001. pmid: 32801862
[36]	Westin SN, Moore K, Chon HS, et al. Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase Ⅲ DUO-E Trial[J]. J Clin Oncol, 2024, 42(3):283-299. doi: 10.1200/JCO.23.02132.