Takahiro Yamazaki

Table S3 contains all statistically significant DEGs from RNAseq data

Table S2 contains all the information related to mass spectrometry

Table S5 contains all the primers used in this study

Table S1 describes all the human ascites samples analyzed

Table S4 describes the organoids used in this study

Figure S1. (a) Effect of dietary iron levels on ovarian cancer progression. Figure S2. Flow cytometry gating strategy for the analysis of peritoneal cells from mice bearing ID8Defb29/Vegfa tumors that were treated with deferiprone as single agent or in combination with cisplatin. Figure S3. (a-f) Wild-type female mice were implanted with ID8-Defb29/Vegfa tumors and treated as described in Fig 2 d. Figure S4. (a) Representative images of NKp46 staining on the entire omentum. Figure S5. (a) MTT assays for ID8-Defb29/Vegfa, PPNM, and MP cells treated with different concentrations of deferiprone for 12, 24, and 48 hours. Figure S6. (a) Human ovarian cancer cell lines were treated with deferiprone for 48 hours and expression of the indicated genes was analyzed by qRT-PCR. Colors indicate fold change (FC) upon deferiprone treatment compared with vehicle control. Figure S7. (a-b) Mitochondrial iron was traced using mito-ferrogreen in iron-overloaded ID8-Defb29/Vegfa cells that were exposed to deferiprone (100 µM) or vehicle control. Figure S8. (a) Schematic representation of treatment regimens under IFNAR1 blockade related to Fig. 6 a-c.

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.

Table S2 contains all the information related to mass spectrometry

Table S1 describes all the human ascites samples analyzed