Harnessing the Embryo Antitumor Factor NEPN for Broad-Spectrum Cancer Immunotherapy via Dual Modulation of Tumor Progression and Immune Suppression

Modifying the tumor microenvironment to target malignant cells and spare healthy cells may be an alternative approach to cancer therapy. Early-stage embryos have been shown to reprogram metastatic tumor cells and prevent tumor formation of several types of cancers, including melanoma, leukemia, and neuroblastoma. However, embryonic factors that suppress tumors in early embryos have not been identified. Here we show that the embryonic secretory factor NEPN suppresses cancer progression and enhances tumor-infiltrating T cells by modulating HSP27 and ARG1 through TGFβ1 signaling, together with broader regulation of tumor-promoting and immune-modulating cytokines. Importantly, NEPN strengthens immune responses and cell death in not only non-solid tumor but also solid tumors by increasing T cell infiltration and activity in the tumor microenvironment. The ability of NEPN to boost immune responses within the tumor microenvironment establishes it as a promising therapeutic candidate for cancer immunotherapy.