{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:37:59Z","timestamp":1787312279211,"version":"build-2736575974"},"reference-count":110,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032579","name":"Beijing Medical Award Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100032579","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Cyclin-dependent kinase 4 and 6 inhibitors (CDK4\/6 inhibitors) combined with endocrine therapy have become a therapeutic backbone for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, yet durable disease control is frequently limited by intrinsic and acquired resistance. Canonical tumor-cell mechanisms, including retinoblastoma-pathway escape, cyclin E-cyclin-dependent kinase 2 (CDK2) activation, endocrine adaptation, and phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling, explain only part of this failure because they do not fully capture dynamic immune and stromal remodeling. Preclinical and translational studies indicate that early CDK4\/6 inhibition can enhance antigen presentation, activate interferon-related programs, restrain regulatory T cells, and promote a T-cell-inflamed state. These effects are conditional and may not persist during prolonged treatment. Sustained therapy can instead drive heterogeneous resistant niches characterized by stromal remodeling, myeloid recruitment, checkpoint adaptation, and T-cell dysfunction. This immune-state dependence provides a rationale for immune checkpoint blockade, although clinical combinations have shown mixed efficacy and clinically relevant hepatic, pulmonary, and hematologic toxicities. Sequential or lead-in strategies therefore warrant prospective evaluation. Oxidative phosphorylation (OXPHOS) and redox adaptation may sustain selected resistant states and expose context-dependent ferroptotic vulnerabilities. Ferroptosis may connect tumor-cell killing with immune regulation, whereas nanomedicine may improve tumor-selective delivery. Both strategies remain largely preclinical and require further evaluation of pharmacokinetics, biodistribution, toxicity, manufacturability, and immune-cell safety. This Review distinguishes intrinsic from acquired resistance across interpatient, intratumoral, spatial, and temporal dimensions. It integrates tumor-cell escape with cytokine, immune, stromal, vascular, and metabolic remodeling and summarizes emerging therapeutic strategies. We further propose a candidate biomarker-informed framework that integrates genomic profiling, spatial immune architecture, circulating biomarkers, T-cell receptor (TCR) dynamics, transcriptomic and single-cell analyses, artificial intelligence (AI)-assisted multimodal integration, and longitudinal sampling. This framework is intended to support biomarker development and prospective trial design rather than current clinical decision-making, providing a translational basis for testing state-informed and sequence-aware therapeutic strategies.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1923129","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:22:38Z","timestamp":1787311358000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cyclin-dependent kinase 4 and 6 inhibitors and the breast cancer immune ecosystem: immune remodeling, resistance, and therapeutic reprogramming"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuhan","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingze","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaochun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxi","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haolu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, West China Ya\u2019an Hospital, Sichuan University","place":["Ya\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41417-024-00747-x","article-title":"Recent progress of CDK4\/6 inhibitors' current practice in breast cancer","volume":"31","author":"Wang","year":"2024","journal-title":"Cancer Gene Ther"},{"key":"B2","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.cytogfr.2023.10.001","article-title":"CDK4\/6 inhibition in hormone receptor-positive\/HER2-negative breast cancer: Biological and clinical aspects","volume":"75","author":"Wekking","year":"2024","journal-title":"Cytokine Growth Factor Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2018.07.002","article-title":"CDK4\/6 inhibition in cancer: Beyond cell cycle arrest","volume":"28","author":"Goel","year":"2018","journal-title":"Trends Cell Biol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nature23465","article-title":"CDK4\/6 inhibition triggers anti-tumour immunity","volume":"548","author":"Goel","year":"2017","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-1390","article-title":"The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4\/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer","volume":"10","author":"Wander","year":"2020","journal-title":"Cancer Discov"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0264","article-title":"The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial","volume":"8","author":"O'Leary","year":"2018","journal-title":"Cancer Discov"},{"key":"B7","doi-asserted-by":"publisher","first-page":"4221","DOI":"10.1038\/s41467-023-40022-5","article-title":"Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers","volume":"14","author":"El-Botty","year":"2023","journal-title":"Nat Commun"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0915","article-title":"CDK4\/6 inhibition augments antitumor immunity by enhancing T-cell activation","volume":"8","author":"Deng","year":"2018","journal-title":"Cancer Discov"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-1425","article-title":"Potent cell-cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, phase II neoadjuvant study in HR+\/HER2- breast cancer","volume":"26","author":"Hurvitz","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2132","DOI":"10.1038\/s41467-025-56279-x","article-title":"Cellular interactions within the immune microenvironment underpins resistance to cell cycle inhibition in breast cancers","volume":"16","author":"Griffiths","year":"2025","journal-title":"Nat Commun"},{"key":"B11","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s12943-025-02226-9","article-title":"Single-cell RNA sequencing identifies molecular biomarkers predicting late progression to CDK4\/6 inhibition in patients with HR+\/HER2- metastatic breast cancer","volume":"24","author":"Luo","year":"2025","journal-title":"Mol Cancer"},{"key":"B12","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/s41523-024-00625-7","article-title":"Cell-cycle inhibition and immune microenvironment in breast cancer treated with ribociclib and letrozole or chemotherapy","volume":"10","author":"Pascual","year":"2024","journal-title":"NPJ Breast Cancer"},{"key":"B13","doi-asserted-by":"publisher","first-page":"11659","DOI":"10.1038\/s41467-025-66590-2","article-title":"Palbociclib and endocrine therapy diminish adaptive anti-tumor immunity in early breast cancer: The NeoRHEA phase 2 study","volume":"16","author":"Papagiannis","year":"2025","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.113059","article-title":"Pirfenidone inhibits CCL2-mediated Treg chemotaxis induced by palbociclib and fulvestrant in HR+\/HER2- breast cancer","volume":"142","author":"Li","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-025-01007-z","article-title":"IL-17A-secreting \u03b3\u03b4 T cells promote resistance to CDK4\/CDK6 inhibitors in HR+HER2- breast cancer via CX3CR1+ macrophages","volume":"6","author":"Petroni","year":"2025","journal-title":"Nat Cancer"},{"key":"B16","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/s00262-024-03695-5","article-title":"Neutrophil-activating secretome characterizes palbociclib-induced senescence of breast cancer cells","volume":"73","author":"Favaretto","year":"2024","journal-title":"Cancer Immunol Immunother"},{"key":"B17","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1038\/s41523-022-00482-2","article-title":"Abemaciclib in combination with pembrolizumab for HR+, HER2- metastatic breast cancer: Phase 1b study","volume":"8","author":"Rugo","year":"2022","journal-title":"NPJ Breast Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007126","article-title":"Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial)","volume":"11","author":"Masuda","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-010430","article-title":"Phase I study of ribociclib (CDK4\/6 inhibitor) with spartalizumab (PD-1 inhibitor) with and without fulvestrant in metastatic hormone receptor-positive breast cancer or advanced ovarian cancer","volume":"13","author":"Garrido-Castro","year":"2025","journal-title":"J Immunother Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20220729","article-title":"PD-1 blockade and CDK4\/6 inhibition augment nonoverlapping features of T cell activation in cancer","volume":"220","author":"Ali","year":"2023","journal-title":"J Exp Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2021.1916243","article-title":"Low-dose CDK4\/6 inhibitors induce presentation of pathway specific MHC ligands as potential targets for cancer immunotherapy","volume":"10","author":"Charles","year":"2021","journal-title":"Oncoimmunology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.116676","article-title":"CDK4\/6 inhibition reprograms the breast cancer immunopeptidome via Rb-dependent chromatin and transcriptomic remodeling","volume":"44","author":"Minati","year":"2025","journal-title":"Cell Rep"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1540","article-title":"Inhibition of CDK4\/6 promotes CD8 T-cell memory formation","volume":"11","author":"Heckler","year":"2021","journal-title":"Cancer Discov"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1554","article-title":"CDK4\/6 inhibition promotes antitumor immunity through the induction of T-cell memory","volume":"11","author":"Lelliott","year":"2021","journal-title":"Cancer Discov"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.970457","article-title":"Palbociclib impairs the proliferative capacity of activated T cells while retaining their cytotoxic efficacy","volume":"14","author":"Arndt","year":"2023","journal-title":"Front Pharmacol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108944","article-title":"Metabolic modulation by CDK4\/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors","volume":"35","author":"Uzhachenko","year":"2021","journal-title":"Cell Rep"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202511330","article-title":"CDK4\/6 inhibition induces CD8+ T cell antitumor immunity via MIF-induced functional orchestration of tumor-associated macrophages","volume":"13","author":"He","year":"2026","journal-title":"Adv Sci (Weinh)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/s41389-023-00475-1","article-title":"CDK4\/6 inhibitors and the pRB-E2F1 axis suppress PVR and PD-L1 expression in triple-negative breast cancer","volume":"12","author":"Shrestha","year":"2023","journal-title":"Oncogenesis"},{"key":"B29","doi-asserted-by":"publisher","first-page":"4254","DOI":"10.1038\/s41467-025-58552-5","article-title":"Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion","volume":"16","author":"Yan","year":"2025","journal-title":"Nat Commun"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-25-0946","article-title":"Single-cell transcriptomics reveals immune landscape dynamics in metastatic hormone receptor-positive breast cancer treated with abemaciclib and endocrine therapy","volume":"32","author":"Strawser","year":"2026","journal-title":"Clin Cancer Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1007\/s11427-021-2140-8","article-title":"Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4\/6 inhibitor in breast cancer that can be reversed by PI3K\/mTOR inhibitors","volume":"66","author":"Cai","year":"2023","journal-title":"Sci China Life Sci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1007\/s10549-024-07376-w","article-title":"Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice","volume":"207","author":"Bhave","year":"2024","journal-title":"Breast Cancer Res Treat"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00174-z","article-title":"Distinct CDK6 complexes determine tumor cell response to CDK4\/6 inhibitors and degraders","volume":"2","author":"Wu","year":"2021","journal-title":"Nat Cancer"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.1038\/s41467-024-46495-2","article-title":"PRMT5 is an actionable therapeutic target in CDK4\/6 inhibitor-resistant ER+\/RB-deficient breast cancer","volume":"15","author":"Lin","year":"2024","journal-title":"Nat Commun"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-2307","article-title":"ESR1 Y537S and D538G mutations drive resistance to CDK4\/6 inhibitors in estrogen receptor-positive breast cancer","volume":"31","author":"Lin","year":"2025","journal-title":"Clin Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00215-7","article-title":"Serial single-cell genomics reveals convergent subclonal evolution of resistance as early-stage breast cancer patients progress on endocrine plus CDK4\/6 therapy","volume":"2","author":"Griffiths","year":"2021","journal-title":"Nat Cancer"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15061908","article-title":"Stromal senescence following treatment with the CDK4\/6 inhibitor palbociclib alters the lung metastatic niche and increases metastasis of drug-resistant mammary cancer cells","volume":"15","author":"Gallanis","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.216747","article-title":"CD63+ cancer-associated fibroblasts confer CDK4\/6 inhibitor resistance to breast cancer cells by exosomal miR-20","volume":"588","author":"Sun","year":"2024","journal-title":"Cancer Lett"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s44320-025-00104-6","article-title":"Blocking cancer-fibroblast mutualism inhibits proliferation of endocrine therapy resistant breast cancer","volume":"21","author":"Griffiths","year":"2025","journal-title":"Mol Syst Biol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/s41523-025-00767-2","article-title":"Baseline cell cycle and immune profiles indicate CDK4\/6 inhibitor response in metastatic HR\u2009+\u2009\/HER2- breast cancer","volume":"11","author":"Tzetzo","year":"2025","journal-title":"NPJ Breast Cancer"},{"key":"B41","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1158\/0008-5472.CAN-24-1211","article-title":"Distant metastases of breast cancer resemble primary tumors in cancer cell composition but differ in immune cell phenotypes","volume":"85","author":"Kuett","year":"2025","journal-title":"Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.02.053","article-title":"The CDK4\/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade","volume":"22","author":"Schaer","year":"2018","journal-title":"Cell Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104010","article-title":"Immune effects of CDK4\/6 inhibitors in patients with HR+\/HER2- metastatic breast cancer: Relief from immunosuppression is associated with clinical response","volume":"79","author":"Scirocchi","year":"2022","journal-title":"EBioMedicine"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002084","article-title":"Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4\/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer","volume":"9","author":"Egelston","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B45","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.ejca.2021.11.025","article-title":"Treatment with ribociclib shows favourable immunomodulatory effects in patients with hormone receptor-positive breast cancer-findings from the RIBECCA trial","volume":"162","author":"Peuker","year":"2022","journal-title":"Eur J Cancer"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-0433","article-title":"CDK4\/6 inhibition sensitizes intracranial tumors to PD-1 blockade in preclinical models of brain metastasis","volume":"30","author":"Nayyar","year":"2024","journal-title":"Clin Cancer Res"},{"key":"B47","doi-asserted-by":"publisher","first-page":"3817","DOI":"10.1038\/s41467-019-11729-1","article-title":"Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4\/6 inhibitor-resistant HER2-positive breast cancer","volume":"10","author":"Wang","year":"2019","journal-title":"Nat Commun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-026-03786-w","article-title":"CSF1R inhibitors mitigate CDK4\/6 inhibitor-induced immunosuppression to increase antitumor immunity in HR+\/HER2- breast cancer","volume":"45","author":"Li","year":"2026","journal-title":"Oncogene"},{"key":"B49","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/s10495-026-02381-4","article-title":"Targeting CDK4\/6 potentiates the efficacy of anti-CD47 therapy via modulating the suppressive function of tumor-associated macrophages","volume":"31","author":"Chen","year":"2026","journal-title":"Apoptosis"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-24-1158","article-title":"RANK pathway inhibition sensitizes triple-negative breast cancer to CDK4\/6 inhibitors and enhances immune response","volume":"24","author":"Gomes","year":"2025","journal-title":"Mol Cancer Ther"},{"key":"B51","article-title":"IL25+ macrophages are a key determinant of treatment resistance of IL17RB+ breast cancer","volume":"13","author":"Ozaki","year":"2023","journal-title":"Am J Cancer Res"},{"key":"B52","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/s12929-025-01173-3","article-title":"CDK4\/6 inhibitors synergize with radiotherapy to prime the tumor microenvironment and enhance the antitumor effect of anti-PD-L1 immunotherapy in triple-negative breast cancer","volume":"32","author":"Yang","year":"2025","journal-title":"J BioMed Sci"},{"key":"B53","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1007\/s00018-025-06056-2","article-title":"CA9+ cancer-associated fibroblasts cooperate with SPP1+ tumor-associated macrophages driving immune resistance in triple-negative breast cancer","volume":"83","author":"Ma","year":"2026","journal-title":"Cell Mol Life Sci"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-026-03075-9","article-title":"SPP1-positive macrophages drive trastuzumab resistance in HER2-positive breast cancer","author":"Wang","year":"2026","journal-title":"Cell Commun Signal"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2025-014421","article-title":"Spatial immune atlas of breast cancer brain metastasis reveals CD163+ macrophage reprogramming associated with immune escape","volume":"14","author":"Zhu","year":"2026","journal-title":"J Immunother Cancer"},{"key":"B56","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13058-025-02192-6","article-title":"The spatial immune landscape predicts outcome and reveals the central role of tumor-associated macrophages in inflammatory breast cancer biology","volume":"28","author":"Van Berckelaer","year":"2026","journal-title":"Breast Cancer Res"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-16-0319","article-title":"Stromal senescence by prolonged CDK4\/6 inhibition potentiates tumor growth","volume":"15","author":"Guan","year":"2017","journal-title":"Mol Cancer Res"},{"key":"B58","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1007\/s11033-023-09119-4","article-title":"The role of CXCL1 in crosstalk between endocrine resistant breast cancer and fibroblast","volume":"51","author":"Pandithar","year":"2024","journal-title":"Mol Biol Rep"},{"key":"B59","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/s41420-023-01658-w","article-title":"Nifuroxazide boosts the anticancer efficacy of palbociclib-induced senescence by dual inhibition of STAT3 and CDK2 in triple-negative breast cancer","volume":"9","author":"Wang","year":"2023","journal-title":"Cell Death Discov"},{"key":"B60","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/s12967-023-03964-4","article-title":"Cellular senescence in the response of HR+ breast cancer to radiotherapy and CDK4\/6 inhibitors","volume":"21","author":"Klapp","year":"2023","journal-title":"J Transl Med"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-025-02183-7","article-title":"Spatial and temporal dynamics of cancer-associated fibroblast niches in breast cancer","volume":"28","author":"Pantaleo","year":"2026","journal-title":"Breast Cancer Res"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-25-0709","article-title":"Stromal cell subsets modulate T-cell infiltration in early breast cancer","volume":"6","author":"Chen","year":"2026","journal-title":"Cancer Res Commun"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.4143\/crt.2025.145","article-title":"Proteomic analysis identifies association of periostin, a matricellular protein, with high tumor stroma and immune exclusion in triple-negative breast cancer","volume":"58","author":"Jeon","year":"2026","journal-title":"Cancer Res Treat"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-026-02326-4","article-title":"Highly CD81-expressing stromal cells characterize a tumor-suppressive immune microenvironment in invasive breast cancer","author":"Nakao","year":"2026","journal-title":"Breast Cancer Res"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2026.01.006","article-title":"Increased Meflin expression in cancer-associated fibroblasts restrains tumor cell proliferation and shapes vessel-rich stroma in triple-negative breast cancer","volume":"196","author":"Sakai","year":"2026","journal-title":"Am J Pathol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1172\/JCI188839","article-title":"Dual targeting of CDK4\/6 and CDK7 augments tumor response and antitumor immunity in breast cancer models","volume":"135","author":"Kim","year":"2025","journal-title":"J Clin Invest"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.00925","article-title":"Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer","volume":"37","author":"Turner","year":"2019","journal-title":"J Clin Oncol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11050684","article-title":"Targeting palbociclib-resistant estrogen receptor-positive breast cancer cells via oncolytic virotherapy","volume":"11","author":"Lypova","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B69","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1016\/j.ccell.2021.08.009","article-title":"Expanding control of the tumor cell cycle with a CDK2\/4\/6 inhibitor","volume":"39","author":"Freeman-Cook","year":"2021","journal-title":"Cancer Cell"},{"key":"B70","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1038\/s41467-025-67865-4","article-title":"CDK2 inhibitor BLU-222 synergizes with CDK4\/6 inhibitors in drug resistant breast cancers through p21\/p27 induction","volume":"17","author":"Luo","year":"2026","journal-title":"Nat Commun"},{"key":"B71","doi-asserted-by":"publisher","first-page":"2997","DOI":"10.1038\/s41388-025-03468-z","article-title":"PTEN neddylation aggravates CDK4\/6 inhibitor resistance in breast cancer","volume":"44","author":"Liu","year":"2025","journal-title":"Oncogene"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2024.106517","article-title":"Estrogen receptor regulation of the immune microenvironment in breast cancer","volume":"240","author":"McGuinness","year":"2024","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-24-2492","article-title":"Stabilization of RUNX1 induced by O-GlcNAcylation promotes PDGF-BB-mediated resistance to CDK4\/6 inhibitors in breast cancer","volume":"85","author":"Zhou","year":"2025","journal-title":"Cancer Res"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.13541","article-title":"CDK4\/6 inhibitors induce breast cancer senescence with enhanced anti-tumor immunogenic properties compared with DNA-damaging agents","volume":"18","author":"Lee","year":"2024","journal-title":"Mol Oncol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1170-y","article-title":"CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy","volume":"569","author":"Wang","year":"2019","journal-title":"Nature"},{"key":"B76","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.ccell.2022.02.003","article-title":"CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4","volume":"40","author":"Liao","year":"2022","journal-title":"Cancer Cell"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.01940","article-title":"PACE: A randomized phase II study of fulvestrant, palbociclib, and avelumab after progression on cyclin-dependent kinase 4\/6 inhibitor and aromatase inhibitor for hormone receptor-positive\/human epidermal growth factor receptor-negative metastatic breast cancer","volume":"42","author":"Mayer","year":"2024","journal-title":"J Clin Oncol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1177\/17588359211064653","article-title":"Final results regarding the addition of dendritic cell vaccines to neoadjuvant chemotherapy in early HER2-negative breast cancer patients: clinical and translational analysis","volume":"13","author":"Santisteban","year":"2021","journal-title":"Ther Adv Med Oncol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0040-8","article-title":"Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer","volume":"24","author":"Zacharakis","year":"2018","journal-title":"Nat Med"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-17-0189","article-title":"Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer","volume":"5","author":"Tchou","year":"2017","journal-title":"Cancer Immunol Res"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002194","article-title":"Phase II clinical trial using anti-CD3 \u00d7 anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) consolidation therapy for HER2 negative (0-2+) metastatic breast cancer","volume":"9","author":"Lum","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B82","doi-asserted-by":"publisher","first-page":"9550","DOI":"10.1038\/s41467-024-53837-7","article-title":"Inhibition of GPX4 enhances CDK4\/6 inhibitor and endocrine therapy activity in breast cancer","volume":"15","author":"Herrera-Abreu","year":"2024","journal-title":"Nat Commun"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103304","article-title":"SLC7A11 protects luminal A breast cancer cells against ferroptosis induced by CDK4\/6 inhibitors","volume":"76","author":"Cui","year":"2024","journal-title":"Redox Biol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12646","article-title":"Targeting ferroptosis resistance resensitizes metastatic HR+HER2- breast cancer cells to palbociclib-hormone therapy","volume":"45","author":"Pottier","year":"2025","journal-title":"Cancer Commun (Lond)"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102952","article-title":"RelB-activated GPX4 inhibits ferroptosis and confers tamoxifen resistance in breast cancer","volume":"68","author":"Xu","year":"2023","journal-title":"Redox Biol"},{"key":"B86","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.cmet.2022.09.021","article-title":"Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy","volume":"35","author":"Yang","year":"2023","journal-title":"Cell Metab"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-025-01887-3","article-title":"PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation","volume":"21","author":"Zheng","year":"2025","journal-title":"Nat Chem Biol"},{"key":"B88","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1016\/j.cmet.2021.02.015","article-title":"CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability","volume":"33","author":"Ma","year":"2021","journal-title":"Cell Metab"},{"key":"B89","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1016\/j.cell.2025.12.002","article-title":"Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors","volume":"189","author":"Liu","year":"2026","journal-title":"Cell"},{"key":"B90","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.1016\/j.cmet.2023.09.004","article-title":"Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1","volume":"35","author":"Zhao","year":"2023","journal-title":"Cell Metab"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.7150\/thno.116013","article-title":"Injectable SF-platform orchestrates GPX4-targeted ferroptosis-autophagy-immunogenic circuit for overcoming oxidative resistance in triple-negative breast cancer","volume":"15","author":"Yuan","year":"2025","journal-title":"Theranostics"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2023.122395","article-title":"Ferroptosis-enhanced chemotherapy for triple-negative breast cancer with magnetic composite nanoparticles","volume":"303","author":"Zhang","year":"2023","journal-title":"Biomaterials"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202310309","article-title":"Nanoparticles synergize ferroptosis and cuproptosis to potentiate cancer immunotherapy","volume":"11","author":"Li","year":"2024","journal-title":"Adv Sci (Weinh)"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.7150\/thno.57803","article-title":"An innovative NRF2 nano-modulator induces lung cancer ferroptosis and elicits an immunostimulatory tumor microenvironment","volume":"11","author":"Hsieh","year":"2021","journal-title":"Theranostics"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.7150\/thno.124189","article-title":"Ligand-directed oral lipidic nanoplatform enables sustained ferroptosis and immune reprogramming via multivalent transporter-mediated metronomic delivery","volume":"16","author":"Subedi","year":"2026","journal-title":"Theranostics"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202310565","article-title":"Mesoporous polydopamine targeting CDK4\/6 inhibitor toward brilliant synergistic immunotherapy of breast cancer","volume":"20","author":"Zhou","year":"2024","journal-title":"Small"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.06.015","article-title":"Prognostic significance of early on-treatment evolution of circulating tumor DNA in advanced ER-positive\/HER2-negative breast cancer","volume":"36","author":"Mamann","year":"2025","journal-title":"Ann Oncol"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2025.105506","article-title":"Circulating tumor DNA mutational landscape and dynamics after progression on a CDK4\/6 inhibitor in the PACE phase II trial for metastatic HR-positive\/HER2-negative breast cancer","volume":"10","author":"Jeselsohn","year":"2025","journal-title":"ESMO Open"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(22)00555-1","article-title":"Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial","volume":"23","author":"Bidard","year":"2022","journal-title":"Lancet Oncol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.2c00446","article-title":"Real-time detection of ESR1 mutation in blood by droplet digital PCR in the PADA-1 trial: feasibility and cross-validation with NGS","volume":"94","author":"Callens","year":"2022","journal-title":"Anal Chem"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2502929","article-title":"First-line camizestrant for emerging ESR1-mutated advanced breast cancer","volume":"393","author":"Bidard","year":"2025","journal-title":"N Engl J Med"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(26)00287-1","article-title":"Switching to camizestrant at ESR1 mutation emergence before disease progression during first-line treatment of hormone receptor-positive advanced breast cancer (SERENA-6): extended analysis of a double-blind, placebo-controlled, randomised, phase 3 trial","volume":"27","author":"Turner","year":"2026","journal-title":"Lancet Oncol"},{"key":"B103","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"B104","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/s13059-020-02015-1","article-title":"MOFA+: a statistical framework for comprehensive integration of multi-modal single-cell data","volume":"21","author":"Argelaguet","year":"2020","journal-title":"Genome Biol"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02857-3","article-title":"Towards a general-purpose foundation model for computational pathology","volume":"30","author":"Chen","year":"2024","journal-title":"Nat Med"},{"key":"B106","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/s41467-026-68570-6","article-title":"Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive\/HER2-negative breast cancer: a phase 2 trial","volume":"17","author":"Kong","year":"2026","journal-title":"Nat Commun"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-019-6344-3","article-title":"Comparison of the molecular and cellular phenotypes of common mouse syngeneic models with human tumors","volume":"21","author":"Zhong","year":"2020","journal-title":"BMC Genomics"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10132872","article-title":"MDSC in mice and men: mechanisms of immunosuppression in cancer","volume":"10","author":"Vanhaver","year":"2021","journal-title":"J Clin Med"},{"key":"B109","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ejca.2021.05.035","article-title":"Phase I\/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer","volume":"154","author":"Yuan","year":"2021","journal-title":"Eur J Cancer"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1016\/j.breast.2023.103580","article-title":"Neoadjuvant nivolumab + palbociclib + anastrozole for oestrogen receptor-positive\/human epidermal growth factor receptor 2-negative primary breast cancer: Results from CheckMate 7A8","volume":"72","author":"Jerusalem","year":"2023","journal-title":"Breast"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1923129\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:22:40Z","timestamp":1787311360000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1923129\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,21]]},"references-count":110,"alternative-id":["10.3389\/fimmu.2026.1923129"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1923129","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,21]]},"article-number":"1923129"}}