ARID1A mutation drives gastric tumorigenesis via activating type 2 immune dominant microenvironment.

is a frequently mutated gene in gastric cancers (GCs), particularly in those associated with the Epstein-Barr virus (EBV), which also often shows mutations and silencing. However, the role of these alterations in the development of GC remains unclear. Here, using Cre; ; ; LSL- mice (APP mice), we found that deletion alone promoted a type 2 immune microenvironment marked by the infiltration of type 2 innate lymphoid cells (ILC2s), eosinophils, mast cells, and M2 macrophages via triggering aberrant IL-33-expressing pit lineage differentiation in stem/progenitor cells. Targeting interleukin (IL)-33, IL-13, and ILC2 activation suppressed metaplasia and tumor progression in APP mice. and mutations cooperatively promoted cell proliferation through v-Akt murine thymoma viral oncogene homolog (AKT) phosphorylation at distinct sites. This type 2 immune response was also observed in human GC samples harboring EBV or mutations. In conclusion, type 2 immune microenvironment is a hallmark of -mutated GCs and represents a promising therapeutic target.