AUTHOR=Dai Mingzheng , Chen Shimin , Wang Yuanjing , Fan Jinxuan , Pan Xin , Sang Chenhui , Liu Yuchen , Hu Ming , Ma Leina , Wang Shasha 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1596344

DOI=10.3389/fimmu.2025.1596344

ISSN=1664-3224

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.