Colorectal cancer (CRC) is a common cancer type which develops due to intricate molecular processes, the Transforming Growth Factor-beta (TGF-β) pathway a role in progression. This study investigates the immunological functions of SERPINE1 and its interaction with long non-coding RNA (lncRNA) LINC01705 within the TGF-β pathway, aiming to identify novel therapeutic targets for CRC. We hypothesized that LINC01705 modulates SERPINE1 expression, thereby influencing CRC progression and immune response. To test this hypothesis, we employed bioinformatics analysis of the TCGA-COAD dataset and experimental validation through RT-qPCR. Our findings revealed a significant upregulation of SERPINE1 in CRC, with nine interacting proteins involved in CRC-related processes identified through coexpression network analysis. Moreover, our findings revealed a high prevalence of mutations in SERPINE1, highlighting its potential as a target for immunotherapy. Additionally, we identified a strong correlation between LINC01705 and SERPINE1, with experimental validation confirming their concurrent upregulation in CRC tissues. These results highlight the importance of the SERPINE1/LINC01705 axis as a novel candidate that influence the TGF-β pathway, offering new insights into CRC pathogenesis and providing potential targets for diagnosis and immunotherapy.Copyright © 2025 Elsevier Ltd. All rights reserved.