晚期三阴性乳腺癌免疫治疗研究进展

doi:10.3760/cma.j.cn371439-20260119-00087

摘要/Abstract

摘要：

近年来，免疫检查点抑制剂尤其是靶向程序性死亡受体1/程序性死亡受体配体1信号通路的药物，在晚期三阴性乳腺癌（TNBC）的治疗中显示出良好的抗肿瘤活性，无论单药或联合治疗均可为部分患者带来显著的临床获益。联合治疗策略包括与化疗、靶向治疗（多聚腺苷二磷酸核糖聚合酶抑制剂、血管内皮生长因子受体抑制剂和抗体药物偶联物）、放疗等联合应用，旨在协同增强抗肿瘤免疫应答。一些新型免疫疗法如双特异性抗体、溶瘤病毒、肿瘤疫苗在TNBC的治疗中展现出初步潜力。但TNBC的免疫治疗仍面临疗效异质性显著、耐药机制复杂等挑战，总体有效率尚不理想。系统分析晚期TNBC免疫治疗的临床研究现状与进展，探讨其作用机制、耐药特征及相关应对策略，可为临床实践和科学研究提供参考。

关键词: 三阴性乳腺癌, 免疫疗法, 免疫检查点抑制剂

Abstract:

In recent years，immune checkpoint inhibitors，particularly those targeting the programmed death-1/programmed death-ligand 1 signal pathway，have demonstrated favorable anti-tumor activity in the treatment of advanced triple-negative breast cancer （TNBC）. Both used as a single agent and in combination，they have brought significant clinical benefits to a subset of patients. Combination strategies include co-administration with chemotherapy，targeted therapies （poly ADP-ribose polymerase inhibitors，vascular endothelial growth factor receptor inhibitors，and antibody-drug conjugates），and radiotherapy，with the aim of synergistically enhancing anti-tumor immune responses. Some novel immunotherapies，such as bispecific antibodies，oncolytic viruses and tumor vaccines，have shown initial potential in the treatment of TNBC. Nevertheless，immunotherapy for TNBC faces substantial challenges，including marked heterogeneity in treatment efficacy and complex drug resistance mechanisms，leading to suboptimal overall response rates. Systematically analyzing the current status and advances of clinical research on immunotherapy for advanced TNBC，and exploring its mechanisms of action，characteristics of drug resistance，and corresponding countermeasures，can provide evidence-based references for clinical practice and scientific research.

Key words: Triple negative breast neoplasms, Immunotherapy, Immune checkpoint inhibitors

方海平, 黄毅, 王根和. 晚期三阴性乳腺癌免疫治疗研究进展[J]. 国际肿瘤学杂志, 2026, 53(9): 547-553.

Fang Haiping, Huang Yi, Wang Genhe. Research progress in immunotherapy for advanced triple-negative breast cancer[J]. Journal of International Oncology, 2026, 53(9): 547-553.

参考文献 50

[1]	Bianchini G, De Angelis C, Licata L, et al. Treatment landscape of triple-negative breast cancer-expanded options, evolving needs[J]. Nat Rev Clin Oncol, 2022, 19: 91-113. DOI: 10.1038/s41571-021-00565-2.
[2]	中国医药教育协会肿瘤药物临床研究专家委员会, 中国初级卫生保健基金会乳腺癌专业委员会. 三阴性乳腺癌免疫检查点抑制剂临床应用专家共识(2025版)[J]. 中华医学杂志, 2025, 105(38): 3394-3406. DOI: 10.3760/cma.j.cn112137-20250411-00895.
[3]	Keenan TE, Tolaney SM. Role of immunotherapy in triple-negative breast cancer[J]. J Natl Compr Canc Netw, 2020, 18(4): 479-489. DOI: 10.6004/jnccn.2020.7554.
[4]	Winer EP, Lipatov O, Im SA, et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2021, 22(4): 499-511. DOI: 10.1016/S1470-2045(20)30754-3.
[5]	Duvivier HL, Rothe M, Mangat PK, et al. Pembrolizumab in patients with tumors with high tumor mutational burden: results from the targeted agent and profiling utilization registry study[J]. J Clin Oncol, 2023, 41(33): 5140-5150. DOI: 10.1200/JCO.23.00702.
[6]	He Q, Peng YC, Sun J, et al. Platinum-based chemotherapy and immunotherapy in early triple-negative breast cancer: a meta-analysis and indirect treatment comparison[J]. Front Oncol, 2021, 11: 693542. DOI: 10.3389/fonc.2021.693542.
[7]	Sternschuss M, Yerushalmi R, Saleh RR, et al. Efficacy and safety of neoadjuvant immune checkpoint inhibitors in early-stage triple-negative breast cancer: a systematic review and meta-analysis[J]. Cancer Res Clin Oncol, 2021, 147(11): 3369-3379. DOI: 10.1007/s00432-021-03591-w.
[8]	Tarantino P, Gandini S, Trapani D, et al. Immunotherapy addition to neoadjuvant chemotherapy for early triple negative breast cancer: a systematic review and meta-analysis of randomized clinical trials[J]. Crit Rev Oncol Hematol, 2021, 159: 103223. DOI: 10.1016/j.critrevonc.2021.103223.
[9]	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)乳腺癌诊疗指南2025[M]. 北京: 人民卫生出版社, 2025.
[10]	Gradishar WJ, Moran MS, Abraham J, et al. NCCN guidelines^® insights: breast cancer, version 5.2025[J]. J Natl Compr Canc Netw, 2025, 23(11): 426-436. DOI: 10.6004/jnccn.2025.0053.
[11]	Adams S, Diéras V, Barrios CH, et al. Patient-reported outcomes from the phase Ⅲ IMpassion130 trial of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancer[J]. Ann Oncol, 2020, 31(5): 582-589. DOI: 10.1016/j.annonc.2020.02.003.
[12]	Miles D, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase Ⅲ trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer[J]. Ann Oncol, 2021, 32(8): 994-1004. DOI: 10.1016/j.annonc.2021.05.801.
[13]	Zhang YY, Chen HY, Mo HN, et al. Distinct cellular mechanisms underlie chemotherapies and PD-L1 blockade combinations in triple-negative breast cancer[J]. Cancer Cell, 2025, 43(3): 446-463.e7. DOI: 10.1016/j.ccell.2025.01.007.
[14]	Dent R, André F, Gonçalves A, et al. IMpassion132 double-blind randomised phase Ⅲ trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer[J]. Ann Oncol, 2024, 35(7): 630-642. DOI: 10.1016/j.annonc.2024.04.001.
[15]	Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial[J]. Lancet, 2020, 396(10265): 1817-1828. DOI: 10.1016/S0140-6736(20)32531-9.
[16]	Jiang ZF, Ouyang Q, Sun T, et al. Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial[J]. Nat Med, 2024, 30: 249-256. DOI: 10.1038/s41591-023-02677-x.
[17]	Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation[J]. N Engl J Med, 2017, 377(6): 523-533. DOI: 10.1056/NEJMoa1706450.
[18]	Rugo HS, Cescon DW, Robson ME, et al. KEYLYNK-009: pembrolizumab plus olaparib in locally recurrent inoperable or metastatic triple-negative breast cancer after clinical benefit from first-line pembrolizumab plus chemotherapy[J]. Clin Cancer Res, 2025, 32(5): 883-893. DOI: 10.1158/1078-0432.CCR-25-1818.
[19]	Vinayak S, Tolaney SM, Schwartzberg L, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer[J]. JAMA Oncol, 2019, 5(8): 1132-1140. DOI: 10.1001/jamaoncol.2019.1029.
[20]	Wang L, Zhang LF, Zhao L, et al. VEGFA/NRP-1/GAPVD1 axis promotes progression and cancer stemness of triple-negative breast cancer by enhancing tumor cell-macrophage crosstalk[J]. Int J Biol Sci, 2024, 20(2): 446-463. DOI: 10.7150/ijbs.86085.
[21]	Li Q, Wang YF, Jia WJ, et al. Low-dose anti-angiogenic therapy sensitizes breast cancer to PD-1 blockade[J]. Clin Cancer Res, 2020, 26(7): 1712-1724. DOI: 10.1158/1078-0432.CCR-19-2179.
[22]	Liu JQ, Liu Q, Li Y, et al. Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer: an open-label phase Ⅱ trial[J]. J Immunother Cancer, 2020, 8(1): e000696. DOI: 10.1136/jitc-2020-000696.
[23]	Gion M, Blancas I, Cortez-Castedo P, et al. Atezolizumab plus paclitaxel and bevacizumab as first-line treatment of advanced triple-negative breast cancer: the ATRACTIB phase 2 trial[J]. Nat Med, 2025, 31(8): 2746-2754. DOI: 10.1038/s41591-025-03734-3.
[24]	Chung HC, Saada-Bouzid E, Longo F, et al. Lenvatinib plus pembrolizumab for patients with previously treated, advanced, triple-negative breast cancer: results from the triple-negative breast cancer cohort of the phase 2 LEAP-005 study[J]. Cancer, 2024, 130(19): 3278-3288. DOI: 10.1002/cncr.35387.
[25]	Hu YX, Zhu YX, Qi D, et al. Trop2-targeted therapy in breast cancer[J]. Biomark Res, 2024, 12(1): 82. DOI: 10.1186/s40364-024-00633-6.
[26]	Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG)+pembrolizumab (pembro) vs chemotherapy (chemo)+pembro in previously untreated PD-L1-positive advanced triple-negative breast cancer (TNBC): primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study[J]. J Clin Oncol, 2025, 43(suppl 17): LBA109. DOI: 10.1200/JCO.2025.43.17_suppl.LBA109.
[27]	Ho AY, Shiao S, Kobald SA, et al. PEARL: a phase Ⅰb/Ⅱ biomarker study of adding radiation therapy to pembrolizumab before neoadjuvant chemotherapy in human epidermal growth factor receptor 2-negative breast cancer[J]. J Clin Oncol, 2024, 42(36): 4282-4293. DOI: 10.1200/JCO.24.00003.
[28]	Ho AY, Barker CA, Arnold BB, et al. A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer[J]. Cancer, 2020, 126(4): 850-860. DOI: 10.1002/cncr.32599.
[29]	Syed YY. Catumaxomab: first approval[J]. Drugs, 2025, 85(7): 957-963. DOI: 10.1007/s40265-025-02187-9.
[30]	Muik A, Garralda E, Altintas I, et al. Preclinical characterization and phase Ⅰ trial results of a bispecific antibody targeting PD-L1 and 4-1BB (GEN1046) in patients with advanced refractory solid tumors[J]. Cancer Discov, 2022, 12(5): 1248-1265. DOI: 10.1158/2159-8290.CD-21-1345.
[31]	Li Q, Liu JX, Zhang QY, et al. The anti-PD-L1/CTLA-4 bispecific antibody KN046 in combination with nab-paclitaxel in first-line treatment of metastatic triple-negative breast cancer: a multicenter phase Ⅱ trial[J]. Nat Commun, 2024, 15(1): 1015. DOI: 10.1038/s41467-024-45160-y.
[32]	Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma[J]. J Clin Oncol, 2015, 33(25): 2780-2788. DOI: 10.1200/JCO.2014.58.3377.
[33]	Pérez-Larraya JG, Garcia-Moure M, Labiano S, et al. Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma[J]. N Engl J Med, 2022, 386(26): 2471-2481. DOI: 10.1056/NEJMoa2202028.
[34]	Tang S, Yong LY, Cui Y, et al. Harnessing oncolytic viruses for targeted therapy in triple-negative breast cancer[J]. Int J Med Sci, 2025, 22(9): 2186-2207. DOI: 10.7150/ijms.105683.
[35]	Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer[J]. N Engl J Med, 2022, 386(6): 556-567. DOI: 10.1056/NEJMoa2112651.
[36]	Soliman H, Hogue D, Han H, et al. Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial[J]. Nat Med, 2023, 29(2): 450-457. DOI: 10.1038/s41591-023-02210-0.
[37]	Knutson KL, Abu-Fares H, Keating P, et al. A phase Ⅱ trial to evaluate the safety and immunogenicity of two doses of a folate receptor alpha vaccine in patients with triple-negative breast cancer[J]. Clin Cancer Res, 2026, 32(1): 106-117. DOI: 10.1158/1078-0432.CCR-25-2763.
[38]	Toh U, Sakurai S, Saku S, et al. Early phase Ⅱ study of mixed 19-peptide vaccine monotherapy for refractory triple-negative breast cancer[J]. Cancer Sci, 2020, 111(8): 2760-2769. DOI: 10.1111/cas.14510.
[39]	Tan ZY, Kan C, Sun MQ, et al. Mapping breast cancer microenvironment through single-cell omics[J]. Front Immunol, 2022, 13: 868813. DOI: 10.3389/fimmu.2022.868813.
[40]	Fattori S, Le Roy A, Houacine J, et al. CD25 high effector regulatory T cells hamper responses to PD-1 blockade in triple-negative breast cancer[J]. Cancer Res, 2023, 83(18): 3026-3044. DOI: 10.1158/0008-5472.CAN-23-0613.
[41]	O'Connell BC, Hubbard C, Zizlsperger N, et al. Eganelisib combined with immune checkpoint inhibitor therapy and chemotherapy in frontline metastatic triple-negative breast cancer triggers macrophage reprogramming, immune activation and extracellular matrix reorganization in the tumor microenvironment[J]. J Immunother Cancer, 2024, 12(8): e009160. DOI: 10.1136/jitc-2024-009160.
[42]	Jia HY, Chen XM, Zhang LL, et al. Cancer associated fibroblasts in cancer development and therapy[J]. J Hematol Oncol, 2025, 18(1): 36. DOI: 10.1186/s13045-025-01688-0.
[43]	Hu DD, Li ZQ, Zheng B, et al. Cancer-associated fibroblasts in breast cancer: challenges and opportunities[J]. Cancer Commun (Lond), 2022, 42(5): 401-434. DOI: 10.1002/cac2.12291.
[44]	Serrano García L, Jávega B, Llombart Cussac A, et al. Patterns of immune evasion in triple-negative breast cancer and new potential therapeutic targets: a review[J]. Front Immunol, 2024, 15: 1513421. DOI: 10.3389/fimmu.2024.1513421.
[45]	Yang YY, Wang WD. Recent progress in immune evasion mechanisms of triple-negative breast cancer[J]. J Transl Med, 2025, 23(1): 1314. DOI: 10.1186/s12967-025-07370-w.
[46]	Sánchez-Elsner T, Botella LM, Velasco B, et al. Synergistic coope-ration between hypoxia and transforming growth factor-β pathways on human vascular endothelial growth factor gene expression[J]. J Biol Chem, 2001, 276(42): 38527-38535. DOI: 10.1074/jbc.M104536200.
[47]	Niu MK, Yi M, Wu YZ, et al. Synergistic efficacy of simultaneous anti-TGF-β/VEGF bispecific antibody and PD-1 blockade in cancer therapy[J]. J Hematol Oncol, 2023, 16(1): 94. DOI: 10.1186/s13045-023-01487-5.
[48]	Zhao CH, Shi JH, Chai XL, et al. First-in-human study of ZGGS18, a dual specific antibody targeting VEGF and TGF-β, as monotherapy in patients with advanced solid tumors[J]. J Clin Oncol, 2024, 42(16): 2523. DOI: 10.1200/JCO.2024.42.16_suppl.2523.
[49]	Tan QR, Yin S, Zhou D, et al. Potential predictive and prognostic value of biomarkers related to immune checkpoint inhibitor therapy of triple-negative breast cancer[J]. Front Oncol, 2022, 12: 779786. DOI: 10.3389/fonc.2022.779786.
[50]	Bullock KK, Richmond A. Beyond anti-PD-1/PD-L1: improving immune checkpoint inhibitor responses in triple-negative breast cancer[J]. Cancers (Basel), 2024, 16(12): 2189. DOI: 10.3390/cancers16122189.