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Biosci. (Landmark Ed)"],"abstract":"<jats:p>The advent of immunotherapy, and particularly the development of immune checkpoint inhibitors (ICIs), has revolutionized the landscape of breast cancer treatment, especially for triple-negative breast cancer. However, some patients still do not benefit from immunotherapy. Breast cancer is inherently an immunotherapy \u201ccold\u201d tumor, which results in suboptimal clinical outcomes when ICIs are used as monotherapy. Identifying additional immunotherapeutic targets and drugs, along with developing novel strategies for combination therapy, is crucial for addressing the challenges posed by immunotherapy resistance and tumor immune escape driven by multiple mechanisms. For instance, the combination of the programmed cell death protein 1 inhibitor, pembrolizumab, with chemotherapy has demonstrated remarkable clinical efficacy and is now the preferred first-line treatment for neoadjuvant, adjuvant, and metastatic breast cancer. This review discusses recently developed ICIs and focuses on strategies combining ICIs with chemotherapy, targeted therapy, nanotherapy, and other approaches in breast cancer. This review aims to summarize recent advances in immune checkpoint inhibitor-based combination strategies in breast cancer and to provide insights into improving therapeutic efficacy, overcoming treatment resistance, and ultimately enhancing patient outcomes.<\/jats:p>","DOI":"10.31083\/fbl45995","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:50:51Z","timestamp":1783421451000},"source":"Crossref","is-referenced-by-count":0,"title":["Molecular Mechanisms and Therapeutic Strategies for Immune Checkpoint Inhibitors in Breast Cancer: From Pathogenesis to Precision Medicine"],"prefix":"10.31083","volume":"31","author":[{"given":"Xueqing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiping","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiming","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute (College) of Integrative Medicine, Dalian Medical University, 116044 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2600-9700","authenticated-orcid":true,"given":"Kainan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"},{"name":"Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1672-2190","authenticated-orcid":true,"given":"Man","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University, 116023 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Ren Y, Song J, Li X, Luo N. Rationale and Clinical Research Progress on PD-1\/PD-L1-Based Immunotherapy for Metastatic Triple-Negative Breast Cancer. International Journal of Molecular Sciences. 2022; 23: 8878.","DOI":"10.3390\/ijms23168878"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Tang S, Ning Q, Yang L, Mo Z, Tang S. Mechanisms of immune escape in the cancer immune cycle. International Immunopharmacology. 2020; 86: 106700.","DOI":"10.1016\/j.intimp.2020.106700"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Keenan TE, Tolaney SM. Role of Immunotherapy in Triple-Negative Breast Cancer. Journal of the National Comprehensive Cancer Network. 2020; 18: 479\u2013489.","DOI":"10.6004\/jnccn.2020.7554"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Emens LA. Breast Cancer Immunotherapy: Facts and Hopes. Clinical Cancer Research. 2018; 24: 511\u2013520.","DOI":"10.1158\/1078-0432.CCR-16-3001"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Wang Y, Zhou S, Yang F, Qi X, Wang X, Guan X, et al. Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis. JAMA Oncology. 2019; 5: 1008\u20131019.","DOI":"10.1001\/jamaoncol.2019.0393"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Yu J, Song Y, Tian W. How to select IgG subclasses in developing anti-tumor therapeutic antibodies. Journal of Hematology & Oncology. 2020; 13: 45.","DOI":"10.1186\/s13045-020-00876-4"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Xie X, Chen L, Kong X, Huo Y, Huang W, Huang J, et al. Comparative efficacy and safety of PD-1 versus PD-L1 inhibitors in breast cancer treatment: A systematic review and meta analysis. 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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. Lancet. 2020; 396: 1817\u20131828.","DOI":"10.1016\/S0140-6736(20)32531-9"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Jiang Z, Ouyang Q, Sun T, Zhang Q, Teng Y, Cui J, et al. Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial. Nature Medicine. 2024; 30: 249\u2013256.","DOI":"10.1038\/s41591-023-02677-x"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Schmid P, Cortes J, Pusztai L, McArthur H, K\u00fcmmel S, Bergh J, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. 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Annals of Oncology. 2022; 33: 534\u2013543.","DOI":"10.1016\/j.annonc.2022.02.004"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Mo H, Sun X, Zhai J, Han J, Ge H, Wei Y, et al. 99P Efficacy and safety of toripalimab plus metronomic chemotherapy in HER2-negative metastatic breast cancer. Immuno-Oncology and Technology. 2023; 20: 100571.","DOI":"10.1016\/j.iotech.2023.100571"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Zhu WY, Jin XY. A narrative review of combination therapy of PD-1\/PD-L1 blockade with standard approaches for the treatment of breast cancer: clinical application and immune mechanism. Annals of Palliative Medicine. 2021; 10: 10075\u201310082.","DOI":"10.21037\/apm-21-2062"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. The Lancet Oncology. 2019; 20: 371\u2013382.","DOI":"10.1016\/S1470-2045(18)30812-X"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Ahn HK, Sim SH, Suh KJ, Kim MH, Jeong JH, Kim JY, et al. Response Rate and Safety of a Neoadjuvant Pertuzumab, Atezolizumab, Docetaxel, and Trastuzumab Regimen for Patients With ERBB2-Positive Stage II\/III Breast Cancer: The Neo-PATH Phase 2 Nonrandomized Clinical Trial. JAMA Oncology. 2022; 8: 1271\u20131277.","DOI":"10.1001\/jamaoncol.2022.2310"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Huober J, Barrios CH, Niikura N, Jarz\u0105b M, Chang YC, Huggins-Puhalla SL, et al. Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial. Journal of Clinical Oncology. 2022; 40: 2946\u20132956.","DOI":"10.1200\/JCO.21.02772"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Gianni L, Munzone E, Mansutti M, Bianchini G, Izarzuzaga Y, Caremoli ER, et al. Abstract LBO1-02: Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial. Cancer Research. 2024; 84: LBO1-02.","DOI":"10.1158\/1538-7445.SABCS23-LBO1-02"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Kuemmel S, Graeser M, Schmid P, Reinisch M, Feuerhake F, Volk V, et al. Chemotherapy-free neoadjuvant pembrolizumab combined with trastuzumab and pertuzumab in HER2-enriched early breast cancer (WSG-KEYRICHED-1): a single-arm, phase 2 trial. The Lancet Oncology. 2025; 26: 629\u2013640.","DOI":"10.1016\/S1470-2045(25)00097-X"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Niravath P, Li M, Guan J, Qian W, Nikolo F, Deng J, et al. Abstract RF1-07: Multifactor analysis for pathologic complete response (pCR) in a chemotherapy-free regimen of durvalumab, trastuzumab, and pertuzumab (DTP Trial) in HER2-enriched early breast cancer. Clinical Cancer Research. 2025; 31: RF1-07.","DOI":"10.1158\/1557-3265.SABCS24-RF1-07"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"Pascual J, Turner NC. Targeting the PI3-kinase pathway in triple-negative breast cancer. Annals of Oncology. 2019; 30: 1051\u20131060.","DOI":"10.1093\/annonc\/mdz133"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"Cheng Y, Tian H. Current Development Status of MEK Inhibitors. Molecules. 2017; 22: 1551.","DOI":"10.3390\/molecules22101551"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, et al. Open-label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. JAMA Oncology. 2019; 5: 1132\u20131140.","DOI":"10.1001\/jamaoncol.2019.1029"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Domchek SM, Postel-Vinay S, Im SA, Park YH, Delord JP, Italiano A, et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1\/2, basket study. The Lancet Oncology. 2020; 21: 1155\u20131164.","DOI":"10.1016\/S1470-2045(20)30324-7"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"Rugo H, Robson M, Im SA, Dalenc F, Ruiz EY, Im YH, et al. 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Cancer Cell. 2021; 39: 989\u2013998.e5.","DOI":"10.1016\/j.ccell.2021.05.009"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Hatem S, Hargis J, Elias A, Lee A, Swart R, Dahkil S, et al. Abstract P5-16-02: Updated efficacy, safety and translational data from MARIO-3, a phase II open-label study evaluating a novel triplet combination of eganelisib (IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC). Cancer Research. 2022; 82: P5-16-02.","DOI":"10.1158\/1538-7445.SABCS21-P5-16-02"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Liu J, Wang Y, Tian Z, Lin Y, Li H, Zhu Z, et al. Multicenter phase II trial of Camrelizumab combined with Apatinib and Eribulin in heavily pretreated patients with advanced triple-negative breast cancer. 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ASTEFANIA: adjuvant ado-trastuzumab emtansine and atezolizumab for high-risk, HER2-positive breast cancer. Future Oncology. 2022; 18: 3563\u20133572.","DOI":"10.2217\/fon-2022-0485"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"Loi S, Schneeweiss A, Song E, Harries M, De Laurentiis M, Li Y, et al. 329TiP KATE3: A phase III study of trastuzumab emtansine (T-DM1) in combination with atezolizumab or placebo in patients with previously treated HER2-positive and PD-L1\u2013positive locally advanced or metastatic breast cancer. Annals of Oncology. 2021; 32: S509.","DOI":"10.1016\/j.annonc.2021.08.612"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"Schmid P, Wysocki P, Ma C, Park YH, Fernandes R, Lord S, et al. Abstract PD11-09: PD11-09 Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced\/metastatic triple-negative breast cancer (a\/mTNBC): updated results from BEGONIA, a phase 1b\/2 study. Cancer Research. 2023; 83: PD11-09.","DOI":"10.1158\/1538-7445.SABCS22-PD11-09"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Tolaney SM, de Azambuja E, Emens LA, Loi S, Pan W, Huang J, et al. 276TiP ASCENT-04\/KEYNOTE-D19: Phase III study of sacituzumab govitecan (SG) plus pembrolizumab (pembro) vs treatment of physician\u2019s choice (TPC) plus pembro in first-line (1L) programmed death-ligand 1-positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC). Annals of Oncology. 2022; 33: S664\u2013S665.","DOI":"10.1016\/j.annonc.2022.07.1860"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"Garrido-Castro AC, Kim SE, Desrosiers J, Nanda R, Carey LA, Clark AS, et al. SACI-IO HR+: A randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive\/HER2-negative breast cancer. Journal of Clinical Oncology. 2024; 42: LBA1004\u2013LBA1004.","DOI":"10.1200\/JCO.2024.42.17_suppl.LBA1004"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"Barroso-Sousa R, Zanudo JGT, Li T, Reddy SM, Emens LA, Kuntz TM, et al. Nivolumab plus low-dose ipilimumab in hypermutated HER2-negative metastatic breast cancer: a phase II trial (NIMBUS). Nature Communications. 2025; 16: 4430.","DOI":"10.1038\/s41467-025-59695-1"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"Nederlof I, Isaeva OI, Bakker N, De Graaf M, Salgado RF, Klioueva N, et al. LBA13 Nivolumab and ipilimumab in early-stage triple negative breast cancer (TNBC) with tumor-infiltrating lymphocytes (TILs): First results from the BELLINI trial. Annals of Oncology. 2022; 33: S1382.","DOI":"10.1016\/j.annonc.2022.08.007"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"Cortes M, Salgado AC, Murillo SM, Blancas I, Cortez P, Plaza IC, et al. Safety interim analysis (SIA) of atractib: A phase 2 trial of first-line (1L) atezolizumab (A) in combination with paclitaxel (P) and bevacizumab (B) in metastatic triple-negative breast cancer (mTNBC). Journal of Clinical Oncology. 2022; 40: 1084.","DOI":"10.1200\/JCO.2022.40.16_suppl.1084"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"Chen L, Zhimin S, Wang Z, Yang W, Jiang Y, Wu S, et al. The overall survival analysis of FUTURE-C-PLUS: Combination of famitinib with camrelizumab plus nab-paclitaxel as first-line treatment for advanced, immunomodulatory triple-negative breast cancer\u2014An open-label, single-arm, phase 2 trial. Journal of Clinical Oncology. 2023; 41: 1086.","DOI":"10.1200\/JCO.2023.41.16_suppl.1086"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"Fan L, Wang ZH, Ma LX, Wu SY, Wu J, Yu KD, et al. Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial. The Lancet Oncology. 2024; 25: 184\u2013197.","DOI":"10.1016\/S1470-2045(23)00579-X"},{"key":"ref67","doi-asserted-by":"publisher","unstructured":"Brufsky A, Kim SB, Zvirbule Z, Dirix LY, Eniu AE, Carabantes F, et al. Phase II COLET study: Atezolizumab (A) + cobimetinib (C) + paclitaxel (P)\/nab-paclitaxel (nP) as first-line (1L) treatment (tx) for patients (pts) with locally advanced or metastatic triple-negative breast cancer (mTNBC). Journal of Clinical Oncology. 2019; 37: 1013.","DOI":"10.1200\/JCO.2019.37.15_suppl.1013"},{"key":"ref68","doi-asserted-by":"publisher","unstructured":"Pilones KA, Joseph A, Vatner R, Formenti S, Demaria S. Radiation Therapy Sensitizes a Poorly Immunogenic Breast Cancer to PD-1 Blockade. International Journal of Radiation Oncology, Biology, Physics. 2014; 90: S58.","DOI":"10.1016\/j.ijrobp.2014.05.203"},{"key":"ref69","doi-asserted-by":"publisher","unstructured":"Voorwerk L, Slagter M, Horlings HM, Sikorska K, van de Vijver KK, de Maaker M, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nature Medicine. 2019; 25: 920\u2013928.","DOI":"10.1038\/s41591-019-0432-4"},{"key":"ref70","doi-asserted-by":"publisher","unstructured":"Ho AY, Barker CA, Arnold BB, Powell SN, Hu ZI, Gucalp A, et al. A phase 2 clinical trial\u202fassessing the\u202fefficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer. Cancer. 2020; 126: 850\u2013860.","DOI":"10.1002\/cncr.32599"},{"key":"ref71","doi-asserted-by":"publisher","unstructured":"Ahmed KA, Kim Y, Arrington JA, Kim S, DeJesus M, Soyano AE, et al. Nivolumab and Stereotactic Radiosurgery for Patients With Breast Cancer Brain Metastases: A Nonrandomized, Open-Label Phase 1b Study. Advances in Radiation Oncology. 2021; 6: 100798.","DOI":"10.1016\/j.adro.2021.100798"},{"key":"ref72","doi-asserted-by":"publisher","unstructured":"Nguyen AT, Shiao SL, McArthur HL. Advances in Combining Radiation and Immunotherapy in Breast Cancer. Clinical Breast Cancer. 2021; 21: 143\u2013152.","DOI":"10.1016\/j.clbc.2021.03.007"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"Li Z, Lai X, Fu S, Ren L, Cai H, Zhang H, et al. Immunogenic Cell Death Activates the Tumor Immune Microenvironment to Boost the Immunotherapy Efficiency. Advanced Science. 2022; 9: e2201734.","DOI":"10.1002\/advs.202201734"},{"key":"ref74","doi-asserted-by":"publisher","unstructured":"Li Z, Cai H, Li Z, Ren L, Ma X, Zhu H, et al. A tumor cell membrane-coated self-amplified nanosystem as a nanovaccine to boost the therapeutic effect of anti-PD-L1 antibody. Bioactive Materials. 2022; 21: 299\u2013312.","DOI":"10.1016\/j.bioactmat.2022.08.028"},{"key":"ref75","doi-asserted-by":"publisher","unstructured":"Liu L, Wang Y, Miao L, Liu Q, Musetti S, Li J, et al. Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer. Molecular Therapy. 2018; 26: 45\u201355.","DOI":"10.1016\/j.ymthe.2017.10.020"},{"key":"ref76","doi-asserted-by":"publisher","unstructured":"Zhu J, Yu M, Chen L, Kong P, Li L, Ma G, et al. Enhanced antitumor efficacy through microwave ablation in combination with immune checkpoints blockade in breast cancer: A pre-clinical study in a murine model. Diagnostic and Interventional Imaging. 2018; 99: 135\u2013142.","DOI":"10.1016\/j.diii.2017.12.011"},{"key":"ref77","doi-asserted-by":"publisher","unstructured":"Zhou W, Yu M, Mao X, Pan H, Tang X, Wang J, et al. Landscape of the Peripheral Immune Response Induced by Local Microwave Ablation in Patients with Breast Cancer. Advanced Science. 2022; 9: e2200033.","DOI":"10.1002\/advs.202200033"},{"key":"ref78","doi-asserted-by":"publisher","unstructured":"Wang Y, Zhang X, Wang Y, Zhao W, Li H, Zhang L, et al. Application of immune checkpoint targets in the anti-tumor novel drugs and traditional Chinese medicine development. Acta Pharmaceutica Sinica B. 2021; 11: 2957\u20132972.","DOI":"10.1016\/j.apsb.2021.03.004"},{"key":"ref79","doi-asserted-by":"publisher","unstructured":"Yu YX, Wang S, Liu ZN, Zhang X, Hu ZX, Dong HJ, et al. Traditional Chinese medicine in the era of immune checkpoint inhibitor: theory, development, and future directions. Chinese Medicine. 2023; 18: 59.","DOI":"10.1186\/s13020-023-00751-7"},{"key":"ref80","doi-asserted-by":"publisher","unstructured":"Wang X, Jing J. Cancer Immunotherapy in Combination with Radiotherapy and\/or Chemotherapy: Mechanisms and Clinical Therapy. MedComm. 2025; 6: e70346.","DOI":"10.1002\/mco2.70346"},{"key":"ref81","doi-asserted-by":"publisher","unstructured":"Vranic S, Cyprian FS, Gatalica Z, Palazzo J. PD-L1 status in breast cancer: Current view and perspectives. Seminars in Cancer Biology. 2021; 72: 146\u2013154.","DOI":"10.1016\/j.semcancer.2019.12.003"},{"key":"ref82","doi-asserted-by":"publisher","unstructured":"Wei Y, Ge H, Qi Y, Zeng C, Sun X, Mo H, et al. Predictive circulating biomarkers of the response to anti-PD-1 immunotherapy in advanced HER2 negative breast cancer. Clinical and Translational Medicine. 2025; 15: e70255.","DOI":"10.1002\/ctm2.70255"},{"key":"ref83","doi-asserted-by":"publisher","unstructured":"Qiu P, Yu X, Zheng F, Gu X, Huang Q, Qin K, et al. Advancements in liquid biopsy for breast Cancer: Molecular biomarkers and clinical applications. Cancer Treatment Reviews. 2025; 139: 102979.","DOI":"10.1016\/j.ctrv.2025.102979"},{"key":"ref84","doi-asserted-by":"publisher","unstructured":"Yu X, Song L, Cen L, Cao B, Tao R, Shen Y, et al. Pan-cancer \u03b3\u03b4 TCR analysis uncovers clonotype diversity and prognostic potential. Cell Reports Medicine. 2024; 5: 101764.","DOI":"10.1016\/j.xcrm.2024.101764"},{"key":"ref85","doi-asserted-by":"publisher","unstructured":"Taylor BC, Sun X, Gonzalez-Ericsson PI, Sanchez V, Sanders ME, Wescott EC, et al. NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer. Cancer Discovery. 2024; 14: 290\u2013307.","DOI":"10.1158\/2159-8290.CD-23-0519"},{"key":"ref86","doi-asserted-by":"publisher","unstructured":"Zou Y, Zhang H, Liu F, Chen ZS, Tang H. Intratumoral microbiota in orchestrating cancer immunotherapy response. Journal of Translational Internal Medicine. 2025; 12: 540\u2013542.","DOI":"10.1515\/jtim-2024-0038"},{"key":"ref87","doi-asserted-by":"publisher","unstructured":"Huang L, Li Y, Zhang C, Jiang A, Zhu L, Mou W, et al. Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors. NPJ Biofilms and Microbiomes. 2025; 11: 180.","DOI":"10.1038\/s41522-025-00819-2"},{"key":"ref88","doi-asserted-by":"publisher","unstructured":"van Wilpe S, Tolmeijer SH, Koornstra RHT, de Vries IJM, Gerritsen WR, Ligtenberg M, et al. Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity. Cancers. 2021; 13: 2249.","DOI":"10.3390\/cancers13092249"},{"key":"ref89","doi-asserted-by":"publisher","unstructured":"Emens LA, Molinero L, Loi S, Rugo HS, Schneeweiss A, Di\u00e9ras V, et al. Atezolizumab and nab-Paclitaxel in Advanced Triple-Negative Breast Cancer: Biomarker Evaluation of the IMpassion130 Study. Journal of the National Cancer Institute. 2021; 113: 1005\u20131016.","DOI":"10.1093\/jnci\/djab004"},{"key":"ref90","doi-asserted-by":"publisher","unstructured":"Jin M, Fang J, Peng J, Wang X, Xing P, Jia K, et al. PD-1\/PD-L1 immune checkpoint blockade in breast cancer: research insights and sensitization strategies. 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