Spatially resolved niche and tumor microenvironmental alterations in gastric cancer peritoneal metastases

Peritoneal metastases (PM) in gastric cancer (GC) portend a poor prognosis, yet our understanding of tumor microenvironmental (TME) characteristics associated with GCPM remain limited. Here, we analyzed intrinsic genomic alterations and transcriptomic programs predictive of GCPM in a prospective cohort of 248 patients, identifying CDH1, PIGR, and ELF3 mutations as predictors. By inspecting the spatial dynamics of the TME, we find that tumor compartment infiltration of pro-tumorigenic cell types such as inflammatory cancer-associated fibroblasts (CAFs) predict peritoneal recurrence. Next, in a cross-sectional study of 205 samples from 55 patients, distinct pathways and immune compositions in GCPM relative to liver metastases highlight the TME's significance in transcoelomic metastases. Notably, several putative therapeutic targets exhibited distinct expression patterns between PTs and PMs. We also observed increased immune infiltration in GCPMs treated with systemic immunotherapy and intraperitoneal chemotherapy. Our findings highlight transcriptomic variations and niche reprogramming in the GCPM peritoneal environment, revealing roles of myeloid dendritic cells, effector memory CD8+ T cells, and CAFs in metastatic progression. ### Competing Interest Statement Funding J. J. Zhao supported by the National University Health System Seed Fund (NUHSRO/2024/008/RO5+6/Seed-Sep23/01), National University Hospital Junior Research Award 2023 (JRA/Sep23/002), and Deans Research Development Award awarded by the Yong Loo Lin School of Medicine, National University of Singapore. J. C. A. Ong is supported by the National Medical Research Council Clinician Scientist-Individual Research Grant (MOH-CIRG21jun-0005) and Clinician Scientist Award (INV category) (MOH-CSAINV22jul-0005). D. K. A. Chia is supported by the ExxonMobil-NUS Research Fellowship, the National University Health System (NUHSRO/2022/057/RO5+6/Seed-Mar/02 and the National Medical Research Council (NMRC/RTF/MH 095:003\008-332). R. Sundar is supported by the National Medical Research Council (NMRC/TA/0014/2020). F. Pietrantonio is supported by AIRC (Associazione Italiana per la Ricerca sul Cancro), IG 2019 number 23624. P.Tan is supported by the National Research Foundation, Singapore, and Singapore Ministry of Health National Medical Research Council under its Open Fund-Large Collaborative Grant (OF-LCG) (MOH-OFLCG18May-0003) and the Singapore Gastric Cancer Consortium. His work was also supported by the National Medical Research Council grant MOH-000967. All other authors do not have any funding sources to declare. The funders of the study had no role in study design, data collection, analysis, interpretation, or writing of the manuscript. Disclosures S. J. Klempner has served a consultant/advisory role for Bristol Myers Squibb, Merck, Eli Lilly, Astellas, Daiichi-Sankyo, Pieris, Natera, Novartis, AstraZeneca, Mersana, Sanofi-Aventis, Servier, and Coherus. SJK reports stock/equity in Turning Point Therapeutics. SJK reports travel support from ASCO, ESMO. P. Tan reports other support from Tempus Healthcare outside the submitted work. M. Bijlsma reports having received research funding from Celgene, Frame Therapeutics, and Lead Pharma, and has acted as a consultant to Servier and Olympus. S.Blum has been a paid consultant to Two River Consulting and Third Rock Ventures. He has equity positions in Kronos Bio, 76Bio, and Allogene Therapeutics. R. Sundar reports grants from National Medical Research Council (NMRC) during the conduct of the study, as well as other support from Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, Eli Lilly, Roche, AstraZeneca, DKSH, MSD, Paxman Coolers, Natera, Astellas, GSK, Ipsen outside the submitted work. All other authors do not have any conflict of interest to declare.