Petroni, GiuliaGiuliaPetroniGalassi, ClaudiaClaudiaGalassiGouin, Kenneth H.Kenneth H.GouinChen, Hsiang-HanHsiang-HanChenBuqué, AitziberAitziberBuquéBloy, NormaNormaBloyYamazaki, TakahiroTakahiroYamazakiSato, AiAiSatoBeltrán-Visiedo, ManuelManuelBeltrán-VisiedoCampia, GinevraGinevraCampiaJiménez-Cortegana, CarlosCarlosJiménez-CorteganaShah, AagamAagamShahKirchmair, AlexanderAlexanderKirchmairMassa, ChiaraChiaraMassaWickenhauser, ClaudiaClaudiaWickenhauserde Andrea, Carlos EduardoCarlos Eduardode AndreaNavarro-Rubio, BelénBelénNavarro-RubioSerrano-Mendioroz, IrantzuIrantzuSerrano-MendiorozNavarro Manzano, EstherEstherNavarro ManzanoSatty, Alexandra M.Alexandra M.SattyRippon, BradyBradyRipponFinotello, FrancescaFrancescaFinotelloTrajanoski, ZlatkoZlatkoTrajanoskiZhou, Xi KathyXi KathyZhouScandura, Joseph M.Joseph M.ScanduraGarcía-Martínez, ElenaElenaGarcía-MartínezAyala de la Peña, FranciscoFranciscoAyala de la PeñaRodríguez-Ruiz, María EsperanzaMaría EsperanzaRodríguez-RuizSánchez-Margalet, VíctorVíctorSánchez-MargaletSeliger, BarbaraBarbaraSeligerde la Cruz-Merino, LuisLuisde la Cruz-MerinoBasho, Reva K.Reva K.BashoShiao, Stephen L.Stephen L.ShiaoMcArthur, Heather L.Heather L.McArthurFormenti, Silvia C.Silvia C.FormentiKnott, Simon R.V.Simon R.V.KnottGalluzzi, LorenzoLorenzoGalluzzi2025-09-052025-09-052025-07-07https://publica.fraunhofer.de/handle/publica/49493610.1038/s43018-025-01007-zResistance 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.enjournal article