LAUSR

Dear Editor, Immune-directed therapeutic approaches have changed the paradigm of cancer treatment. The tumor-immune microenvironment [1] is a dynamic milieu consisting of heterogeneous metabolic conditions such as low oxygen, nutrient deficiency, acidity, and interactions betweenmultiple cell types. In particular, immune cells in the tumor microenvironment are vulnerable to cellular dysfunctions (because of metabolic reprogramming [2]) and engage in intercellular communications with neighboring cells, thereby contributing to a tolerogenic and incompetent immune environment. Here, we evaluated 84 metabolic pathways in 12,422 single cells from patients with gastric cancer (GC) [3] and predicted immune checkpoint blockade (ICB) responses associated with cell type-specific metabolic features using clinical outcome data from 45 GC patients treated with ICB at the Samsung Medical Center (the SMC cohort) (Supplementary Table S1) [4] andmolecular subtype data from 497 GC patients treated at Yonsei SeveranceHospital (the Yonsei cohort) (Supplementary Table S2) [5]. We first analyzed differences in the metabolic pathways in bulk GC samples between ICB responders and non-responders. The clinical data of the SMC cohort was subjected to systematic bioinformatics analyses for seven metabolic signatures [6]. In the responder group, biosynthetic pathways associated with amino acid synthesis (P = 0.026) and nucleotide synthesis (P = 0.006) were significantly enriched (Figure 1A). Differences in 84 metabolic pathways were also examined (Supplementary Figure S1A). The responder and non-responder groups demonstrated significant differences in 10 metabolic path-