THBS1 Targets Tumor‐Associated Macrophages to Regulate Gastric Cancer Peritoneal Metastasis via Metabolic Reprogramming

Abstract

This study aimed to identify the role of thrombospondin 1 (THBS1) in gastric cancer (GC) with peritoneal metastasis (PM) as a model of aberrant interorgan communication between gastric carcinoma and the peritoneal microenvironment. Bulk, single‐cell, and spatial transcriptomics were performed to identify mechanisms underlying M2 macrophage‐mediated GC with PM. RNA immunoprecipitation confirmed binding between RNA‐protein and GC9811‐P cells. A GC9811‐P‐tumor‐associated macrophage (TAM) co‐culture system was established. Macrophage polarization markers were performed after THBS1 knockdown, using cell counting kit‐8, flow cytometry, migration and invasion assays, and glucose/lipid metabolism detection. Meanwhile, an enzyme‐linked immunosorbent assay was performed to measure inflammatory factors. In vivo, a BALB/C GC peritoneal dissemination mouse model was employed to investigate the regulatory role of THBS1 in GC with PM progression. Transcriptomic analysis identified SEMA7A, THBS1, and HBEGF as key mediators of intercellular communication between M2 macrophages and malignant cells, with RIP assay confirming the targeted binding of THBS1 to SDC4. THBS1 knockdown suppressed GC9811‐P cell proliferation, migration, and invasion; inhibited M2 polarization; and reduced mitochondrial membrane potential, ATP levels, and HIF‐1ɑ, PFKFB3, ABHD5, and MGLL expression. In vivo, THBS1 knockdown reduced peritoneal metastatic tumor burden. THBS1 regulates pathological interorgan communication between GC cells and the peritoneal niche by targeting TAMs through metabolic reprogramming, thereby providing a potential therapeutic target for GC with PM and insights into interorgan metastasis mechanisms.