A Malignant Subpopulation of H2AFZ+ Cells Interacts with Myeloid Cells to Promote an Anti-inflammatory Microenvironment and Drive Hepatic Metastasis, Revealing an Immunotherapeutic Strategy for Pancreatic Ductal Adenocarcinoma

PURPOSE: Hepatic metastasis is the leading cause of death in pancreatic ductal adenocarcinoma (PDAC). However, the underlying cellular and molecular programs remain poorly understood, leading to limited therapeutics for this disease. EXPERIMENTAL DESIGN: Here, we integrated single-cell RNA sequencing data from paired primary tumors (PTs) and hepatic metastases (HMs), along with bulk RNA sequencing and immunohistochemistry data from hundreds of patients to elucidate metastasis-associated programs. RESULTS: Our analysis identified a metastasis-prone malignant subpopulation, which is associated with a higher risk of hepatic metastasis and a transitional plastic state. This malignant subpopulation represents a poorly differentiated and highly proliferative phenotype, with H2AFZ potentially contributing to this phenomenon. Moreover, the presence of tumor cells in the liver was accompanied by an increased abundance of M2 macrophages, regulatory T cells, and exhausted T cells in HMs compared with adjacent tissues, indicative of a shift toward an immune suppressive environment. Notably, within the tumor environment of HMs, exhausted T cells exhibited elevated expression of PDCD1 and LAG3. The combined therapy targeting these two genes effectively inhibited tumor growth in mouse models of metastatic PDAC. CONCLUSIONS: In conclusion, we reveal a metastasis-associated malignant subpopulation and provide a promising therapeutic strategy for metastatic PDAC.