ObjectiveTo investigate the interplay between immune cell infiltration and extracellular matrix (ECM) remodeling in diffuse gastric cancer (DGC), and to identify novel diagnostic biomarkers and therapeutic targets. MethodsTranscriptomic data of DGC patients from The Cancer Genome Atlas (TCGA) were analyzed to screen potential regulatory factors associated with immune-related and ECM receptor-related pathways. Differential expression of the identified regulator was evaluated between tumor and adjacent tissues. Bioinformatic analyses assessed its correlations with immune cell infiltration, ECM dynamics, and prognosis. Clinical validation was performed using 90 paraffin-embedded DGC tissue samples (tumor and matched adjacent tissues) from our hospital (January 2017 to December 2019). Immunohistochemistry (IHC) was applied to examine protein expression, followed by analysis of its associations with immune infiltration, clinicopathological features, and survival. Additionally, quantitative real-time PCR was conducted on 10 paired fresh DGC samples (2024 cohort) to validate mRNA expression. The significance level was set at α=0.05. ResultsCollagen type I alpha 1 chain (COL1A1) was identified as a key regulator linked to both immune suppression and ECM receptor pathways. COL1A1 was significantly upregulated in DGC tumors versus adjacent tissues (P<0.001) and correlated with poor prognosis [HR(95%CI)=2.9(1.21, 7.30), P=0.017]. Its expression negatively correlated with CD8+ T-cell infiltration (CIBERSORT: r=−0.17, P < 0.001; xCELL: r=−0.32, P<0.001) but positively associated with M2 tumor-associated macrophages (TAMs) (CIBERSORT: r=0.32; xCELL: r=0.24; both P<0.001). Clinical validation confirmed elevated COL1A1 protein/mRNA levels in tumors (both P<0.001). High COL1A1 protein expression predicted worse overall survival (P<0.001) and served as an independent risk factor for postoperative survival (HR=6.607, P<0.001) COL1A1 positively correlated with CD163 (M2 TAM marker, r=0.76, P< 0.001) and inversely with CD8+ T cells (r=−0.84, P<0.001). ConclusionCOL1A1 is a pivotal mediator of immune evasion and ECM dysregulation in DGC, significantly impacting long-term survival. Targeting COL1A1 may represent a promising therapeutic strategy for DGC.