Tumor-Associated Macrophages Undergo Specific Lineage Transition to Elicit the Immune Evasion of the Ascitic Tumor Cells in Gastric Cancer with Peritoneal Metastasis

In gastric cancer with peritoneal carcinomatosis (PM-GC), one of the deadliest cancers, the aggressiveness of metastatic tumor cells induces severe therapeutic resistance. However, whether and how the tumor cell-extrinsic tumor microenvironment (TME) is involved in the therapeutic failure remains unknown. Here, by leveraging multiple analyses, including single-cell transcriptional profiling of ascites and phenotypic analysis of ascites-disseminated tumor cells (aDTCs) and their in vitro cultured cell lines, we revealed the immunosuppressive TME in PM-GC ascites and its contribution to aDTC dissemination and immune evasion. Tumor-associated macrophages (TAMs) underwent a lineage transition from CTShigh to C1Qhigh. CTS high TAM precursors initially attracted the metastatic tumor cells to ascites, thereafter transitioning terminally to the C1Qhigh TAMs to trigger the overproliferation and PD-L1-mediated immune escape of the aDTCs. Our findings provide new insights into TAM differentiation and its crosstalk with tumor cells and may contribute to the development of potential TAM-targeted immunotherapies for PM-GC.