Abstract
BACKGROUND: Colon adenocarcinoma (COAD) is a prevalent and aggressive malignancy with limited treatment options, particularly for advanced stages. While programmed death-ligand 1 (PD-L1) inhibition, has emerged as an appealing therapeutic approach for COAD, its effectiveness as a monotherapy is hindered by high tumor heterogeneity. Identifying novel therapeutic targets to boost the efficacy of PD-L1-based immunotherapy in COAD is crucial to improving clinical outcomes. Matrix metalloproteinase-2 (MMP-2), traditionally known for its role in tumor invasion, metastasis, and angiogenesis, has not been thoroughly investigated in the relationship to immunotherapy for COAD. This work aims to investigate the potential involvement of MMP-2 in the immune microenvironment of COAD and explore its possible role as a target to enhance the therapeutic efficacy of anti-PD-L1-based immunotherapy. METHODS: This study employed a comprehensive bioinformatics analysis of publicly available datasets to investigate the correlation between MMP-2 expression and PD-L1 levels in COAD. Additionally, we evaluated the impact of MMP-2 expression on patient survival and prognosis. To validate these findings, in vitro experiments were conducted to assess the effect of MMP-2 inhibition on PD-L1 expression in colon cancer cell lines. We also analyzed the association between MMP-2 expression and tumor-infiltrating lymphocytes (TILs) to elucidate the immunological landscape of COAD. RESULTS: Our bioinformatic analysis revealed a novel positive correlation between MMP-2 expression and PD-L1 level in COAD, indicating that higher MMP-2 level is associated with increased PD-L1 expression. Furthermore, in COAD patients, elevated MMP-2 expression was linked to poor overall survival and prognosis. In vitro experiments demonstrated that inhibiting MMP-2 significantly reduced PD-L1 expression in SW480 cells, suggesting that MMP-2 plays a regulatory function in immune evasion. In addition, a novel negative relationship between MMP-2 expression and the presence of TILs was identified, underscoring MMP-2's potential role in modifying the COAD immunological landscape. CONCLUSION: This work shows for the first time that MMP-2 not only contributes to tumor progression but also plays a critical role in the immunosuppressive microenvironment of COAD. The demonstrated association between MMP-2 and PD-L1 expression, along with its effect on TILs, indicates that MMP-2 is a promising alternative target for improving the efficacy of anti-PD-L1 immunotherapy. Targeting MMP-2 may offer a novel avenue for overcoming resistance to conventional immunotherapies, potentially improving treatment outcomes in COAD patients.