Tumor-associated neutrophils in gastric cancer: dual roles with promising prognostic and therapeutic potential

Despite the traditional view of neutrophils as primarily antibacterial cells, emerging evidence has highlighted their significant involvement in cancer progression and the modulation of the tumor microenvironment (TME). Tumor-associated neutrophils (TANs) have been recognized as key players in various malignancies, exerting both pro-tumorigenic and anti-tumorigenic effects that can ultimately influence disease outcomes. In gastric cancer (GC.), one of the most prevalent and lethal digestive system malignancies worldwide, TANs facilitate tumor progression through chronic inflammation, genomic instability, immunosuppression, angiogenesis, and metastasis. Their functional states exist along a continuum shaped by cytokines, microbial signals, exosomal transfer, and stromal interactions, resulting in context-dependent functions across disease stages and molecular subtypes. Elevated peripheral neutrophil-to-lymphocyte ratio (NLR) and specific TAN subsets are associated with adverse clinical outcomes in many cohorts, although protective associations have been observed in defined settings. This review synthesizes current knowledge on TAN origin, recruitment, phenotypic heterogeneity, and bidirectional crosstalk within the multicellular GC TME. It further evaluates their prognostic potential and examines emerging opportunities for therapeutic modulation. A deeper mechanistic understanding of TAN biology may support the development of neutrophil-directed strategies to overcome therapeutic resistance and improve outcomes in this heterogeneous malignancy. GC is one of the most common and deadly cancers worldwide. Neutrophils are white blood cells that normally fight infections. In recent years, researchers have discovered that these cells also play important roles inside tumors. When neutrophils enter a stomach tumor, they are called TANs. TANs can behave in two opposite ways. In some situations, they help the body fight the cancer by attacking tumor cells and supporting the immune system. In other situations, they help the cancer grow, spread to other parts of the body, create new blood vessels that feed the tumor, and weaken the immune response. The tumor’s local environment, including signals from cancer cells, other immune cells, bacteria, and chemical messengers, decides which role the neutrophils take. High numbers of certain TANs, or a high ratio of neutrophils to other immune cells in the blood, are often linked to more advanced disease and shorter survival. However, in specific types of GC or in certain locations within the tumor, higher TAN numbers can sometimes be associated with better outcomes. This shows that the effect of these cells depends heavily on context. Understanding how TANs work opens new possibilities. Measuring them may help doctors predict how a patient’s cancer will behave. In the future, treatments that reduce the harmful effects of TANs or reprogram them to fight the cancer could improve the results of chemotherapy and immunotherapy. More research is still needed before these approaches become part of routine care.