Cancer is a predominant culprit behind worldwide death and accounts for up to 10 million deaths every year. Chemotherapy is the primary therapeutic method employed for cancer in clinical settings and is essential in controlling tumor progression. Despite the advances in this field, tumor invasion and metastasis during treatment remain a significant cause of treatment failure. Nevertheless, the underlying mechanisms involving such a disappointing phenomenon are still not fully elucidated. Vinorelbine (VNB) extends the lifespan of many cancer patients in the clinic as an emerging chemotherapy drug approved by Food and Drug Administration (FDA). However, VNB-induced tumor metastasis is still an intractable problem, which may be closely related to the abnormal oxidative stress generated during VNB-mediated treatment. Hence, the study aims to construct a reductive nanosystem loaded with VNB, called VNB-VNP, to improve cancer cure rates and reduce tumor metastasis. With the reductive component vitamin E, VNB-VNP can effectively reduce oxidative stress and significantly outperform free VNB in preventing tumor progression. The transcriptome analysis shows that VNB-VNP can alleviate the over-expression of ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), which may be the main reason why VNB-VNP can inhibit tumor invasion and metastasis. Overall, the research designs a new platform for VNB treatment, which demonstrates promising efficacy in inhibiting neoplastic progression and identifies a new mechanism associated with VNB-induced tumor metastasis, which may offer several valuable references for enhancing chemotherapy efficacy in clinical anti-tumor therapy.