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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1536545
This article is part of the Research Topic Precision Oncology in Checkpoint Immunotherapy: Leveraging Predictive Biomarkers for Personalized Treatment View all 11 articles

Integrative Analysis of Semaphorins Family Genes in Colorectal Cancer: Implications for Prognosis and Immunotherapy

Provisionally accepted
Jiahao Zhu Jiahao Zhu 1Benjie Xu Benjie Xu 1Zhixing Wu Zhixing Wu 2Zhiwei Yu Zhiwei Yu 1Shengjun Ji Shengjun Ji 3*Jie Lian Jie Lian 1Haibo Lu Haibo Lu 1
  • 1 Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
  • 2 University of Liverpool, Liverpool, North West England, United Kingdom
  • 3 Department of Radio-Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China

The final, formatted version of the article will be published soon.

    Background: Semaphorins (SEMAs), originally identified as axon guidance factors, have been found to play crucial roles in tumor growth, invasiveness, neoangiogenesis, and the modulation of immune responses. However, the prognostic value of SEMA-related genes in colorectal cancer (CRC) remains unclear.We applied a novel machine learning framework that incorporated 10 machine learning algorithms and their 101 combinations to construct a SEMAs-related score (SRS).Multi-omics analysis was performed, including single-cell RNA sequencing (scRNA-seq), and spatial transcriptome (ST) to gain a more comprehensive understanding of the SRS. A series of cell experiments were conducted to prove the impact of key genes on CRC biological behavior.Result: A consensus SRS was finally constructed based on a 101-combination machine learning computational framework, demonstrating outstanding performance in predicting overall survival. Moreover, distinct biological functions, mutation burden, immune cell infiltration, and immunotherapy response were observed between the high-and low-SRS groups. scRNA-seq and ST demonstrated unique cellular heterogeneity in CRC. We observed that SRS-high and SRS-low malignant epithelial cells exhibit different biological characteristics. High SRS malignant epithelial cells interact with myeloid and endothelial cells via SPP1 and COL4A2-ITGAV-ITGB8 pathways, respectively. Low SRS cells engage with myeloid and endothelial cells through MIF and JAG1-NOTCH4 pathways. Additionally, knocking down SEMA4C significantly inhibits the proliferation and invasion of CRC cells, while promoting apoptosis in vitro.SRS could serve as an effective tool to predict survival and identify potential patients benefiting from immunotherapy in CRC. It also reveals tumor heterogeneity and provides valuable biological insights in CRC.

    Keywords: Semaphorins, colorectal cancer, Immunotherapy, single-cell sequencing, Spatial transcriptome sequencing

    Received: 29 Nov 2024; Accepted: 10 Feb 2025.

    Copyright: © 2025 Zhu, Xu, Wu, Yu, Ji, Lian and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Shengjun Ji, Department of Radio-Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China

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