Mutation-Immune Crosstalk Contextualizes CAF-Associated ARPC1A Programs and Cisplatin Response in Gastric Cancer

Cisplatin response in gastric cancer is shaped by malignant cell programs, stromal states, and mutation-immune crosstalk, but the CAF subtypes linked to platinum tolerance and their epithelial effectors remain incompletely defined. We integrated single-cell RNA sequencing, epithelial CNV-like inference, fibroblast reclustering, CellChat analysis, signature scoring, hdWGCNA, CAF-epithelial coupling, exploratory GSE14209 evaluation, TCGA-STAD mutation/copy-number contextualization, and DepMap CRISPR virtual knockout analysis, followed by experimental validation in AGS and HGC-27 cells. IGF1+ CXCL12+ CAFs showed resistance-supportive stromal features, and CAF-epithelial coupling prioritized ARPC1A as a tumor epithelial candidate associated with this stromal program. In TCGA-STAD, ARPC1A mutations were rare and consisted of three missense and two frameshift variants without a recurrent hotspot; the mutant tumors were confined to the MSI subtype and showed an immune-activated, high TMB/MSI context, indicating mutation-immune crosstalk rather than a clear mutation-specific CAF, EMT, drug resistance, or cisplatin response phenotype. By contrast, ARPC1A copy-number gain/amplification was more frequent and tracked with ARPC1A expression, CIN enrichment, aneuploidy, and fraction of genome altered. DepMap CRISPR data indicated mostly weak-to-mild baseline ARPC1A dependency in upper GI and gastric/GEJ models. Experimentally, ARPC1A knockdown increased cisplatin sensitivity, promoted cisplatin-induced apoptosis, and suppressed migration and invasion. These findings identify a CAF-associated ARPC1A epithelial program linked to cisplatin response and support a mutation-immune/copy-number framework in which ARPC1A is interpreted mainly through immune-contextual mutation patterns and expression dosage rather than recurrent gain-of-function mutation.