Neutrophil‐Macrophage Interactions Shape Inflammatory Macrophage Remodeling in Gastric Cancer During Chemo‐Immunotherapy

ABSTRACT The tumor microenvironment (TME) in gastric cancer (GC) is a dynamic ecosystem where immune, stromal, and malignant cells influence therapeutic outcomes. Although macrophages and neutrophils are key regulators of the TME, their coordinated responses to distinct treatments remain unclear. In this study, we performed single‐cell RNA sequencing on GC biopsy specimens from treatment‐naïve (TN) patients, as well as patients treated with chemotherapy (C), chemotherapy plus nivolumab (CN), or chemotherapy plus trastuzumab (CT). Comparative analyses revealed marked remodeling of the myeloid compartment, particularly involving the CN group. Neutrophils in the CN group exhibited transcriptional reprogramming, characterized by major histocompatibility complex (MHC) class II expression, inflammatory activation, and enrichment of maturation‐related signatures. Pseudotime and ligand–receptor analyses identified neutrophils as a prominent sender of signals communicating with macrophages via chemokine and cytokine signaling. These neutrophil‐derived signals promoted macrophage polarization toward a CXCL10 + M1‐like phenotype and activated inflammatory signaling pathways. In vivo validation using a syngeneic CT26 mouse model confirmed that neutrophil depletion abolished the antitumor efficacy of combined oxaliplatin and PD‐1 blockade, underscoring the functional importance of this crosstalk. Collectively, our findings demonstrate that PD‐1 blockade combined with chemotherapy reprograms the GC TME by enhancing neutrophil–macrophage interactions, which amplify inflammatory signaling and strengthen antitumor immunity. These results highlight the myeloid‐centered axis as a potential determinant of immunotherapy responses in GC.