Tumor microenvironment remodeling plus immunotherapy could be used in mesenchymal-like tumor with high tumor residual and drug resistant rate.

Epithelial-mesenchymal transition (EMT) is a common process during tumor progression and is always related to residual tumor, drug resistance and immune suppression. However, considering the heterogeneity in EMT process, there is still a need to establish robust EMT classification system with reasonable molecular, biological and clinical implications to investigate whether these unfavorable survival factors are common or unique in different individuals. In our work, we classify tumors with four EMT status, that is, EMT low , EMT mid , EMT high -NOS (Not Otherwise Specified), and EMT high -AKT (AKT pathway overactivation) subtypes. We find that EMT high -NOS subtype is driven by intrinsic somatic alterations. While, EMT high -AKT subtype is maintained by extrinsic cellular interplay between tumor cells and macrophages in an AKT-dependent manner. EMT high -AKT subtype is both unresectable and drug resistant while EMT high -NOS subtype can be treated with cell cycle related drugs. Importantly, AKT activation in EMT high -AKT not only enhances EMT process, but also contributes to the immunosuppressive microenvironment. By remodeling tumor immune-microenvironment by AKT inhibition, EMT high -AKT can be treated by immune checkpoint blockade therapies. Meanwhile, we develop TumorMT website ( http://tumormt.neuroscience.org.cn/ ) to apply this EMT classification and provide reasonable therapeutic guidance.