AUTHOR=Zhong Fei , Mao Shining , Peng Shuangfu , Li Jiaqi , Xie YanTeng , Xia Ziqian , Chen Chao , Sun Aijun , Zhang Shasha , Wang Shiyan 

TITLE=Exploration of SUSD3 in pan-cancer: studying its role, predictive analysis, and biological significance in various malignant tumors in humans

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1521965

DOI=10.3389/fimmu.2025.1521965

ISSN=1664-3224

ABSTRACT=BackgroundThe SUSD3 protein, marked by the Sushi domain, plays a key role in cancer progression, with its expression linked to tumor advancement and patient prognosis. Altered SUSD3 levels could serve as a predictive biomarker for cancer progression. Recognized as a novel susceptibility marker, SUSD3 presents a promising target for antibody-based therapies, offering a potential approach for the prevention, diagnosis, and treatment of breast cancer.MethodsUsing the HPA and GeneMANIA platforms, the distribution of SUSD3 protein across tissues was analyzed, while expression levels in tumor and healthy tissues were compared using The Cancer Genome Atlas data. The TISCH and STOmics DB databases facilitated the mapping of SUSD3 expression in different cell types and its spatial relationship with cancer markers. Univariate Cox regression assessed the prognostic significance of SUSD3 expression in various cancers. Genomic alterations of SUSD3 were explored through the cBioPortal database. The potential of SUSD3 as a predictor of immunotherapy response was investigated using TIMER2.0, and GSEA/GSVA identified related biological pathways. Drugs targeting SUSD3 were identified through CellMiner, CTRP, and GDSC databases, complemented by molecular docking studies. In vitro experiments demonstrated that SUSD3 knockdown in breast cancer cell lines significantly reduced proliferation and migration.ResultsSUSD3 expression variations in pan-cancer cohorts are closely linked to the prognosis of various malignancies. In the tumor microenvironment (TME), SUSD3 is predominantly expressed in monocytes/macrophages and CD4+ T cells. Research indicates a strong correlation between SUSD3 expression and key cancer immunotherapy biomarkers, immune cell infiltration, and immunomodulatory factors. To explore its immune regulatory role, StromalScore, ImmuneScore, ESTIMATE, and Immune Infiltration metrics were employed. Molecular docking studies revealed that selumetinib inhibits tumor cell proliferation. Finally, SUSD3 knockdown reduced cancer cell proliferation and migration.ConclusionThese findings provide valuable insights and establish a foundation for further exploration of SUSD3’s role in pan-carcinomas. Additionally, they offer novel perspectives and potential targets for the development of innovative therapeutic strategies in cancer treatment.