An elevated extracellular matrix (ECM) and interstitial fluid pressure (IFP) in gastric cancer limits the targeting of HER2-expressing cells when radioimmunotherapy (RIT) with Cu-trastuzumab (Cu-TRZ) is utilized. Here, we used Losartan (LOS) to downregulate ECM and IFP in gastric cancer mice model. In our study we treated the gastric cancer mice model with a dose of 40 mg/kg of LOS. We found that the LOS treatment increases a twofold higher Alexa-647-TRZ accumulation which significantly enhanced Cu-TRZ. We determined that the LOS-treated samples exhibited reduced mRNA and protein expression of SERPINE1, a gene associated with the ECM degradation. Additionally, LOS treatment resulted in the downregulated mRNA expression of the TGF-β1 and COL13A1, the genes involved in ECM deposition and an upregulated RNA expression of MMP2, a gene associated with the ECM degradation. There were no significant changes in metastatic markers of N-Cadherin and E-Cadherin. Moreover, our study demonstrates that silencing SERPINE1 increases the activity of the MMP2 and decreases COL13A1 with no effect on the N-cadherin and E-cadherin were observed. Our novel combinational therapy of using Cu-TRZ with LOS is attributed to the downregulation of SERPINE1 targeting ECM and IFP is highly effective for treatment of gastric cancer.