F-box Proteins at the Crossroads of Ubiquitination and Tumor Immunity: Regulatory Networks and Immunotherapy Strategies

Mingzheng Dai^1,2,3Shimin Chen^1,2,3Yuanjing Wang^1,2,3Jinxuan Fan^1,2,3Xin Pan⁴Chenhui Sang³Yuchen Liu³Ming Hu^5*Leina Ma^1,3*Shasha Wang^1,2*

• ¹Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
• ²Qingdao Cancer Institute, Qingdao University, Qingdao, Shandong Province, China
• ³College of Basic Medicine, Qingdao University, Qingdao, China
• ⁴Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China, Jinan, China
• ⁵.Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China, QingdaoQingdao, China

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.