Provided are Zika virus constructs and methods of using Zika virus constructs and Zika viruses to treat subjects in need thereof.

A combination therapeutic strategy employs multiple oncolytic viruses (OVs), grouped and administered based on their virological properties, tumor selectivity, and distinct antigen profiles, to treat malignant tumors. Representative groupings may include members of flaviviruses, each contributing distinct immune modulation and the same modes of tumor cell killing. A predefined treatment schedule involves sequential or concurrent administration of antigenically diverse OVs in multiple cycles, reducing cross-neutralization and sustaining cytolytic pressure on tumors. A pre-characterized OV panel, comprising members from a virus family, RNA and DNA viruses, both wild-type and genetically engineered, serves as a flexible resource for customizing treatment regimens by tumor type, immune landscape, and therapeutic goals. This platform establishes a rational framework for combination OV therapy with improved durability, safety, and clinical effectiveness.