Core Viewpoint - The study reveals that HEBP2-mediated glutamine competition between tumor cells and macrophages dictates the efficacy of immunotherapy in triple-negative breast cancer (TNBC), identifying GSTP1 as a new therapeutic target to enhance treatment outcomes [3][4]. Group 1: Research Findings - The research team developed a single-cell RNA sequencing (scRNA-seq) immune therapy cohort (N=27) and a spatial transcriptomics cohort (N=88) to elucidate the metabolic interactions related to TNBC treatment efficacy [5]. - High expression of HEBP2 in tumor cells, characterized by active glutathione metabolism, and CCL3+ macrophages, characterized by oxidative metabolism, indicate effective immunotherapy, showing a negative correlation in quantity and spatial distribution [5]. - HEBP2 disrupts the cytoplasmic phase separation of the transcription factor FOXA1, promoting its nuclear translocation, which upregulates GSTP1 expression and glutamine consumption in tumor cells [5][6]. Group 2: Implications for Treatment - The metabolic shift induced by HEBP2 leads to ferroptosis in CCL3+ macrophages, impairing anti-tumor immunity [5]. - The use of GSTP1 inhibitors (Ezatiostat) can block this pathway, preventing excessive glutamine consumption by tumor cells, thereby protecting macrophages and restoring anti-tumor immunity, making TNBC more sensitive to cancer immunotherapy (anti-PD-1 monoclonal antibodies) [5][7]. - The findings establish a metabolic checkpoint regulated by the HEBP2/GSTP1 signaling axis, pioneering the assessment of immune metabolic weaknesses at the single-cell level [6][7].