Polyethylene terephthalate nanoplastics promote gastric cancer progression by inhibiting the TNF-α/JAK1/STAT1 signaling pathway and shaping an immunosuppressive microenvironment.

Polyethylene terephthalate (PET), one of the most widely produced plastics used in food packaging, has emerged as a pervasive source of microplastic exposure in humans, with recent evidence confirming its presence in the human stomach. However, the biological consequences of PET nanoplastics (PET-NPs) on gastric carcinogenesis remain largely unexplored. In this study, we systematically investigated the effects of PET-NPs on gastric cancer progression and the underlying molecular and immunological mechanisms. PET-NPs were readily internalized by gastric cancer cells, leading to enhanced cell proliferation, migration, and resistance to Oxaliplatin, accompanied by suppression of apoptosis and immunogenic cell death. In vivo validation using a mouse subcutaneous tumor model further demonstrated that PET-NPs significantly promoted tumor growth. Integrated mechanistic analyses combining transcriptomics, network toxicology, and western blotting revealed that PET-NPs exhibited strong binding affinity to tumor necrosis factor-α (TNF-α), resulting in inhibition of the downstream JAK1/STAT1 signaling pathway. Moreover, PET-NPs profoundly remodeled the tumor immune microenvironment by promoting M2 macrophage polarization, reducing CD8+ T cell infiltration, upregulating immune checkpoint molecules TIGIT and PD-1, and suppressing key antitumor cytokines, including IFN-γ and TNF-α. Collectively, these findings demonstrate that PET-NPs act as a previously underrecognized environmental risk factor that accelerates gastric cancer progression through direct molecular interference and immune suppression, highlighting the potential public health implications of chronic microplastic exposure.