Divergent clonal evolution and tumor microenvironment remodeling shape gastric cancer peritoneal metastasis

Gastric cancer peritoneal metastasis (GCPM) is a distinct clinical entity with a poor prognosis, characterized by aggressive features and limited treatment options. Understanding its molecular biology is critical for developing effective therapies. We performed whole genome and transcriptome sequencing on GCPM samples and partially paired primary gastric cancer (GC) tissues from 14 and 26 patients, respectively. Our analysis reveals substantial intra-patient heterogeneity between GCPM and primary tumors at both genetic and functional levels. Inter-patient variability is observed in mutational overlaps, with some signatures unique to either GCPM or primary tumors. Tumor evolution analysis suggests divergent clonal evolution, with distinct clones specific to GCPM or primary tumors in most patients. Transcriptomic profile reveals a high heterogeneity in the primary tumors, with five tumors presenting GCPM characteristics. The tumor microenvironment (TME) is poorly conserved between primary GC and GCPM, with desert-type primary tumors often transitioning to immune-enriched TMEs in metastases. These findings suggest that immunotherapy resistance in GCPM may arise from factors beyond intrinsic TME characteristics, such as limited drug delivery due to the peritoneal-plasma barrier. Collectively, our results highlight significant molecular and TME heterogeneity between GCPM and primary tumors, emphasizing the need for GCPM-specific stratification and innovative treatment strategies to improve outcomes.