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Review
. 2025 Dec;21(1):2504776.
doi: 10.1080/21645515.2025.2504776. Epub 2025 May 17.

Research hotspots and frontier analysis of the novel immune checkpoint Nectin-4

Yu Qiao  1 , Wanyu Zhao  2 , Yusen Gou  3   4   5 , Yuwei Li  6 , Fang Su  1 , Rui Wang  1 , Jiejun Wang  1 , Haibo Zhang  1 , Lei Sun  3   4   5 , Feng Qian  3   4   5 , Zishu Wang  1
Affiliations
Review

Research hotspots and frontier analysis of the novel immune checkpoint Nectin-4

Yu Qiao et al. Hum Vaccin Immunother. 2025 Dec.

Abstract

Nectin-4 has emerged as a pivotal therapeutic target for antibody-drug conjugates (ADCs), particularly in advanced urothelial carcinoma (aUC) research. Although extensive literature has been reported on Nectin-4, it is worth noting that no studies have yet systematically investigated the hotspots, cutting-edge directions, and tissue expression of this target using a combination of bibliometric analysis and bioinformatics methods. Findings reveal growing interest in Nectin-4's role in cancer immunotherapy and ADC development. Urothelial carcinoma remains the primary focus, with breast and bladder cancers gaining traction. Key research priorities include optimizing ADC safety profiles, particularly managing cutaneous adverse events. Notably, dual targeting strategies combining Nectin-4 with TROP-2 show promise for next-generation ADC therapies. The study highlights evolving clinical needs, from target validation to treatment optimization, positioning Nectin-4 as a versatile biomarker bridging multiple cancer research domains. These insights emphasize the protein's translational potential while underscoring the importance of balancing therapeutic efficacy with toxicity management in ADC development.

Keywords: CiteSpace; Frontiers; Nectin-4; VOSviewer; research hotspots.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
External characteristics of NECTIN4 research and annual publication analysis. (a) Analysis of the input.Zip data using the R-bibliometrix package to obtain the external characteristics of NECTIN4-related literature. (b)Utilizing HiscitePro to acquire the annual publication counts and global average annual citation frequencies and employing origin 2024 to create a dual Y-axis bar-line chart that illustrates the relationship between the annual number of publications and the global average annual citation frequencies.
Figure 2.
Figure 2.
Distribution of NECTIN4 in academic journals. (a) Bradford’s law analysis of core journals using the bibliometrix package. (b) Journal coupling analysis using VOSviewer, with different colors representing clusters. (c) Journal co-citation analysis using VOSviewer, primarily divided into two clusters. (d) Journal dual-map overlay analysis using CiteSpace.
Figure 3.
Figure 3.
Research directions and hotspot analysis. (a) Co-occurrence analysis of author keywords from 2018 to 2024. Nodes with the same color belong to the same cluster, and the node size represents the frequency of the keyword’s occurrence. (b)ggplot2 keyword hotspot matrix analysis. (c) CiteSpace keyword burst analysis.
Figure 4.
Figure 4.
Co-citation analysis of references. (a) Co-citation analysis of references using CiteSpace. The clustering colors transition from cool to warm, representing the average publication year of clusters from older to newer. (b) CiteSpace reference clustering mountain plot.
Figure 5.
Figure 5.
Analysis of research frontiers in 2024–2025. Circular layout analysis using CiteSpace.
Figure 6.
Figure 6.
mRNA and protein expression levels of NECTIN4 in pan-cancer. (a) mRNA expression levels of NECTIN4 in TCGA and GTEx. (b) Protein expression levels of NECTIN4 in pan-cancer. wilcoxon rank sum tests measured p-value.
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