NDV-GT wth hyperacute rejection in cancer therapy

• NDV-GT expresses α-Gal epitopes on tumor cells to trigger hyperacute rejection. • NDV-GT reprograms the TME, enhancing T-cell infiltration and cytokine secretion. • Preliminary clinical data show 90.0% disease control rate with no severe adverse events. • NDV-GT inhibits PI3K/AKT and NF-κB pathways, promoting apoptosis and tumor regression. • CRISPR-engineered macaque HCC model validates translational potential of NDV-GT. Oncolytic viruses (OVs) represent a promising immunotherapy for cancer treatment, though their clinical application is often limited by systemic toxicity and low immunogenicity. To address this, we developed NDV-GT, a genetically engineered Newcastle disease virus that encodes porcine α-1,3-galactosyltransferase. These epitopes are recognized by pre-existing natural antibodies, triggering a hyperacute rejection response characterized by complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Furthermore, NDV-GT modulates the tumor microenvironment by promoting T-cell infiltration and cytokine secretion, converting immunologically “cold” tumors into “hot” ones. Mechanistically, the virus inhibits PI3K/AKT and NF-κB signaling pathways, inducing apoptosis and suppressing tumor proliferation. In a preliminary clinical study of 20 patients with advanced refractory carcinomas, NDV-GT achieved a 90.0% disease control rate with no serious adverse events, underscoring its potential as a novel, safe, and effective oncolytic agent that elicits robust antitumor immunity.