Plasmodium infection inhibits angiogenesis and induces autophagy in melanoma through the PI3K/AKT/mTOR pathway

Melanoma is a highly malignant and metastatic skin tumor, and current treatments exhibit limited efficacy in advanced cases. Plasmodium infection can activate the human immune system. Previous studies have found Plasmodium infection has therapeutic effects on lung cancer and breast cancer. However, this treatment method has never been used on melanoma therapy. The PI3K/AKT/mTOR signaling pathway is crucial for regulating tumor cell autophagy and angiogenesis. Whether this signaling pathway plays a role in malaria parasite infection for treating melanoma remains unclear. A mouse B16F10 melanoma model was established. The subjects were randomly divided into a control group (Mel) and a Plasmodium infection group (Mel + Py). Transmission electron microscopy was employed to examine the morphology of autophagosomes. Hematoxylin and eosin (HE) staining, along with immunohistochemistry(IHC), was utilized to assess histopathological changes in the tumor. Additionally, RT-qPCR and Western blot analyses were performed to evaluate the expression of autophagy-related factors (LC3-II, Beclin-1, Atg5, P62) and angiogenic factors (HIF-1α, VEGF), as well as to measure the phosphorylation levels of the PI3K/AKT/mTOR pathway. Plasmodium infection significantly inhibited melanoma growth, as indicated by a reduction in tumor volume ( p < 0.05). This infection also induced autophagosome formation and autophagic cell death, demonstrated by the up-regulation of LC3-II, Beclin-1, and Atg5 expression, along with the degradation of P62. Concurrently, the infection down-regulated the expression of HIF-1α VEGF and CD31, thereby inhibiting tumor angiogenesis. Mechanistically, the infection specifically decreased the phosphorylation levels of AKT and mTOR (p-AKT and p-mTOR) without altering the total protein levels, suggesting inhibition of the PI3K/AKT/mTOR pathway. Plasmodium infection demonstrates antimelanoma effects by inhibiting the phosphorylation of the PI3K/AKT/mTOR pathway, synergistically inducing autophagic cell death, and suppressing angiogenesis. This investigation offers a novel molecular foundation for Plasmodium -based therapy and may provide new insights into melanoma treatment.