A cDC1 ‐ NK /T‐Malignant Cell Circuit Drives Immunogenic Remodeling Under PD ‐1 Blockade in Gastric Cancer

ABSTRACT The gastric cancer (GC) tumor microenvironment (TME) constitutes a complex and dynamic ecosystem in which immune, stromal, and malignant cells (MCs) collectively shape therapeutic responses. The dynamics of GC TME remodeling in different treatment contexts remain unclear. We performed single‐cell RNA sequencing (scRNA‐seq) of GC biopsy specimens from treatment‐naïve patients (TN) and patients treated with chemotherapy (C), chemotherapy plus nivolumab (CN), or chemotherapy plus trastuzumab (CT), and found that CN treatment enhanced natural killer (NK)/T cell‐associated immunogenicity in GC TMEs. In CN TMEs, MCs upregulate MHC‐I‐ and inflammation‐related genes. Conventional type 1 dendritic cells (cDC1), one subcluster of dendritic cells (DCs), concurrently exhibited activation of antigen‐presentation and T cell‐stimulatory programs, indicating intensified communication between NK/CD8 + T cells and cDC1 in the CN TMEs. The cell–cell interaction analyses uncovered an intensified X‐C Motif Chemokine Ligand 1 (XCL1) ‐ X‐C motif chemokine receptor 1 (XCR1) chemotactic axis linking NK/CD8 + T cells and cDC1, highlighting the formation of “the MCs‐cDC1‐NK/CD8 + T cells circuit” to reinforce antitumor immunity in the CN TMEs. Furthermore, a reduced cytotoxic NK sub‐cluster, which showed high XCL1 expression, was enriched among CN responders, and its transcriptional signature was significantly correlated with favorable survival in the Cancer Genome Atlas GC cohort. Our findings delineate an immunostimulatory circuit driven by NK/CD8 + T‐DCs–MCs interactions to orchestrate the immune cycle under CN therapy in GC TMEs.