136 This study, published in Genes & Diseases by researchers from Nanchang Medical College, The University of Chicago Medical Centre, Chongqing Hospital of Traditional Chinese Medicine, Chongqing Medical University, The First Affiliated Hospital of Chongqing Medical University, The Children’s Hospital of Chongqing Medical University, Nanjing Medical University, Ningbo Medical Centre Li Hui Li Hospital, The University of Agriculture, Peshawar, University of California, Davis, and Shandong Second Medical University, provides a comprehensive synthesis of evidence identifying the G protein-coupled oestrogen receptor (GPER) as a key regulator of endocrine resistance in breast cancer. Unlike classical nuclear oestrogen receptors, GPER mediates rapid, non-genomic oestrogen signalling and activates multiple oncogenic pathways that promote tumour survival, proliferation, and therapeutic escape. The review systematically examines how GPER contributes to resistance across a broad spectrum of endocrine-based treatments, including selective oestrogen receptor modulators, aromatase inhibitors, selective oestrogen receptor degraders, and combination regimens involving CDK4/6 and PI3K/AKT/mTOR inhibitors. Elevated GPER expression is consistently associated with poor therapeutic response, disease recurrence, and unfavourable clinical prognosis. Mechanistically, GPER activation stimulates downstream signalling cascades such as EGFR, MAPK/ERK, PI3K/AKT, cAMP/PKA, and calcium-dependent pathways, enabling tumour cells to maintain oestrogen-responsive growth despite effective blockade of classical oestrogen receptors. Beyond tumour-intrinsic signalling, the review highlights the role of GPER in remodelling the tumour microenvironment. GPER signalling in cancer-associated fibroblasts, immune cells, adipocytes, and endothelial cells enhances epithelial–mesenchymal transition, cancer stem-like properties, angiogenesis, and immune suppression. These microenvironmental changes reinforce endocrine resistance and support metastatic dissemination, underscoring GPER’s role as a coordinator of tumour–stroma interactions. Importantly, the authors emphasise the clinical implications of incorporating GPER into breast cancer classification and treatment strategies. Stratifying patients based on combined ER, HER2, and GPER status may improve risk prediction and guide the selection of combination therapies. The review also discusses emerging therapeutic opportunities, including GPER antagonists, PROTAC-based degraders, and rational combination strategies integrating GPER targeting with endocrine, targeted, or immunotherapies. Despite growing evidence supporting GPER as a therapeutic target, challenges remain, including limited clinical validation, context-dependent signalling effects, and incomplete understanding of GPER interactions with other hormonal and growth factor pathways. The review calls for integrative multi-omics studies and well-designed clinical investigations to clarify these complexities. Overall, this review positions GPER as a central molecular hub linking non-genomic oestrogen signalling to endocrine therapy resistance, offering new insights into breast cancer progression and highlighting promising avenues for improving treatment durability and patient outcomes.