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Review
. 2025 Jun 4:16:1596344.
doi: 10.3389/fimmu.2025.1596344. eCollection 2025.

F-box proteins at the crossroads of ubiquitination and tumor immunity: regulatory networks and immunotherapy strategies

Mingzheng Dai #  1   2   3 , Shimin Chen #  1   2   3 , Yuanjing Wang #  1   2   3 , Jinxuan Fan  1   2   3 , Xin Pan  4 , Chenhui Sang  3 , Yuchen Liu  3 , Ming Hu  5 , Leina Ma  1   2 , Shasha Wang  1   2
Affiliations
Review

F-box proteins at the crossroads of ubiquitination and tumor immunity: regulatory networks and immunotherapy strategies

Mingzheng Dai et al. Front Immunol. .

Abstract

As critical substrate-recognition subunits of the SCF (SKP1-CUL1-F-box) ubiquitin ligase complex, F-box proteins mediate the ubiquitination and subsequent degradation of specific target proteins, playing pivotal roles in cell cycle regulation, signal transduction (e.g., MAPK and NF-κB pathways), and immune homeostasis. F-box proteins have dual regulatory functions in tumorigenesis and immune escape. On one hand, their expression is dynamically modulated by upstream signaling pathways (including PI3K/AKT and Wnt/β-catenin cascades) and epigenetic modifications (such as DNA methylation and histone acetylation), thereby influencing the stability of oncogenic factors (e.g., c-MYC, Cyclin E) or tumor suppressors (e.g., p53). On the other hand, F-box proteins directly regulate tumor immune microenvironments by targeting immune-related molecules for degradation, thereby modulating T-cell activation, macrophage polarization, and immune checkpoint functionality (specifically PD-1/PD-L1 axis and CTLA-4 signaling). This review systematically summarizes the upstream and downstream regulatory networks of F-box proteins, with an emphasis on their molecular mechanisms in tumor immunosuppression. It highlights the potential strategies and drug resistance mechanisms in targeting F-box proteins for combination with immunotherapies, while also discussing future research applications and development directions of F-box proteins. These insights aim to advance the development of novel immunotherapeutic strategies for precision cancer treatment.

Keywords: F-box protein; cancer; immunotherapy strategies; proteasomal degradation; ubiquitination.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
This figure was created in BioRender (https://BioRender.com). Ubiquitination regulates the crosstalk between tumors and the tumor microenvironment.
Figure 2
Figure 2
This figure was created in BioRender (https://BioRender.com). FBXW7 regulates tumor immunity via Ubiquitin-Dependent signaling.
Figure 3
Figure 3
Related miRNA that affect F-box protein expression and their binding sites on 3’-UTR.
See this image and copyright information in PMC

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