Background: ER+ breast cancer patients generally have good prognosis. However, significant relapse rates (i.e., hormone drugs, Tamoxifen/TMX) and the poor response to immune checkpoint blockade (ICB) remain critical issues to be addressed. Thus, exploration of anti-ICB resistant mechanisms and alternative targets is needed to improve therapeutic efficacy. Methods: To investigate potential cross-resistant mechanisms between hormone and ICB therapy, ER+ cell lines T47D and MCF7 cells were chronically-treated with TMX for 6 months, and subjected to RNA-Seq and pathway enrichment analysis. Dysregulation of identified factors were validated via western blotting, RT-qPCR, and flow cytometry. Target factors were then inhibited or depleted by shRNA knockdown (KD) or small-compound inhibition. Identified ICB resistance mechanisms were further elaborated by in vitro co-culture assays, syngeneic mouse models, and immune-profiling of tumor microenvironment (TME). Results: Chronic exposure to TMX activates Type I interferon (IFN-I) signaling, induces IFN I-stimulated gene (ISG) expression, and downregulates the H3K4 demethylase and ISG repressor complex known as RACK7/KDM5C. Chronic TMX also upregulates CEACAM1, a well-known ligand for the immune checkpoint receptor TIM3. Results prompt us to evaluate whether loss of RACK7 combined with TMX treatment may modulate a lymphocyte-attractive (via IFN-I), but T-cell exhaustive (via CEACAM1-TIM3) TME. Indeed, in vitro treatment of TMX under RACK7-KD conditions triggers STING upregulation, TBK1 hyperphosphorylation, and a more pronounced activation of ISGs and CEACAM1. In vivo, TMX combined with RACK7-KD enhances tumor growth in the TS/A (ER+) syngeneic mouse model, while immune-profiling reveal that this combination promotes lymphocyte infiltration with a higher population of terminally exhausted CD8+ T-cells in the TME. Conclusions: Our data demonstrate that the TMX-induced activation of cGAS/STING pathway and RACK7 downregulation coordinately shape the IFN-I and immune checkpoint signaling axes in ER+ breast cancer. This TMX–RACK7–IFN-I regulatory network promotes a lymphocyte-attractive TME via IFN-I signaling activation, whereas induction of inhibitory ligands renders T-cells to be terminally-exhausted and unable to kill tumors. These findings highlight the potential use of TMX’s STING-agonistic effect in re-shaping the “cold” breast cancer TME, and the use of combined TMX and anti-TIM3 or anti-CEACAM1 blockade to improve ICB therapy.