MedImmune

Jul 10, 2025

Resistance to cyclin-dependent kinase 4/6 (CDK4/CDK6) inhibitors leads to treatment failure and disease progression in women with hormone receptor HER2 (HR HER2 ) breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting interleukin-17A (IL-17A)-secreting γδ T cells to mouse HR HER2 BCs following CDK4/CDK6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) toward an immunosuppressive CX3CR1 phenotype associated with resistance. Increased IL-17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of individuals with HR HER2 BC. Circulating γδ T cells and plasma CCL2 levels negatively correlated with progression in an independent series of individuals with HR HER2 BC receiving CDK4/CDK6 inhibitors. Intratumoral γδ T cells were increased in post- versus pretreatment biopsies from individuals with HR HER2 BC relapsing on CDK4/CDK6 inhibitors. CX3CR1 TAMs had negative prognostic impact in women with HR HER2 BC receiving neoadjuvant PD-1 blockage and radiotherapy. Thus, γδ T cells and CX3XR1 TAMs may favor resistance to CDK4/CDK6 inhibitors in individuals with HR HER2 BC. Conflict of interest statement Competing interests: F.F. has been holding research contracts with iOnctura. M.E.R.-R. reports receiving research funding from Roche and Bioncotech. She also has received speaker's bureau honoraria from Bristol Myers Squibb (BMS) and Roche. H.L.M. is/has been holding research contracts with BMS, MedImmune, LLC/AstraZeneca, BTG and Merck and has received consulting/advisory honoraria from Amgen, BMS, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi-Sankyo, Seattle Genetics, AstraZeneca, Gilead, Crown Bioscience and TapImmune. S.C.F. is/has been holding research contracts with Merck, Varian, BMS, Celldex, Regeneron, Eisai and Eli Lilly and has received consulting/advisory honoraria from Bayer, BMS, Varian, Elekta, Regeneron, Eisai, AstraZeneca, MedImmune, Merck US, EMD Serono, Accuray, Boehringer Ingelheim, Roche, Genentech, AstraZeneca, View Ray and Nanobiotix. S.R.V.K. is a founder and consultant at Transomic Technologies and Faeth Therapeutics. L.G. is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom and the Luke Heller TECPR2 Foundation and holds Promontory stock options. All other authors have no conflicts to declare. Similar articles Using bioinformatics and artificial intelligence to map the cyclin-dependent kinase 4/6 inhibitor biomarker landscape in breast cancer. CDK4/6 inhibitors as adjuvant treatment for hormone receptor-positive, HER2-negative early breast cancer: a systematic review and meta-analysis. A bedside-to-bench translational analysis of NF1 alterations and CDK4/6 inhibitor resistance in hormone receptor-positive metastatic breast cancer. Impact of low HER2 expression on response to CDK4/6 inhibitor treatment in advanced HR + /HER2- breast cancer: a multicenter real-world data analysis. Efficacy of Subsequent Treatments After Disease Progression on CDK4/6 Inhibitors in Patients With Hormone Receptor-Positive Advanced Breast Cancer. References Morrison, L., Loibl, S. & Turner, N. C. The CDK4/6 inhibitor revolution—a game-changing era for breast cancer treatment. Nat. Rev. Clin. Oncol. 21, 89–105 (2024). - PubMed DOI Hortobagyi, G. N. et al. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann. Oncol. 36, 149–157 (2025). - PubMed DOI O'Leary, B. et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 8, 1390–1403 (2018). - PubMed PMC DOI Wander, S. A. et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer. Cancer Discov. 10, 1174–1193 (2020). - PubMed PMC DOI Gong, X. et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib. Cancer Cell 32, 761–776 (2017). - PubMed DOI