Recent Insight on Regulations of FBXW7 and Its Role in Immunotherapy

Abstract

SCFFBXW7 E3 ubiquitin ligase complex is a crucial enzyme of the ubiquitin proteasome system that participates in variant activities of cell process, and its component FBXW7 (F-box and WD repeat domain–containing 7) is responsible for recognizing and binding to substrates. The expression of FBXW7 is controlled by multiple pathways at different levels. FBXW7 facilitates the maturity and function maintenance of immune cells via functioning as a mediator of ubiquitination-dependent degradation of substrate proteins. FBXW7 deficiency or mutation results in the growth disturbance and dysfunction of immune cell, leads to the resistance against immunotherapy, and participates in multiple illnesses. It is likely that FBXW7 coordinating with its regulators and substrates could offer potential targets to improve the sensitivity and effects of immunotherapy. Here, we review the mechanisms of the regulation on FBXW7 and its tumor suppression role in immune filed among various diseases (mostly cancers) to explore novel immune targets and treatments.

Mesothelin expression correlates with elevated inhibitory immune activity in patients with colorectal cancer

“…Regarding gene mutation patterns, recent studies have determined that increased mutation in KRAS and FBXW7 have been implicated as immunosuppressive biomarkers that play a role in poor immunotherapeutic responses in CRC. 43 , 44 Additionally, high co-expression of HAVCR2 and MSLN have been shown to be prevalent in several cancers and may also be vulnerabole to the use of CAR-T therapies. Pre-clinical studies have shown the utility of CAR-T therapy in an MSLN high ovarian cancer model.…”

FBXW7 and human tumors: mechanisms of drug resistance and potential therapeutic strategies

“…With tumor-infiltrating immune cells and cancer-associated fibroblasts (CAFs), the tumor microenvironment (TME) has emerged as a central player in cancer drug resistance, which constantly evolves during cancer progression and significantly affects treatment efficiency (Liu et al, 2022). FBXW7 is involved in immune evasion that occurs in anti-tumor immune responses, as well as in the regulation of the immune microenvironment, and its mutation or downregulation is more likely to lead to immunotherapy resistance (Xing et al, 2022). Mutation or loss of function of FBXW7 significantly reduces the infiltration of dendritic cells and immune cells, such as macrophages and CD8 T cells, in the tumor microenvironment, thereby promoting resistance to anti-PD-1 therapy (Gstalder et al, 2020;Ding et al, 2023).…”

“…Similar to CRC, preclinical studies and case reports have shown that deletion of FBXW7 is associated with resistance to anti-PD-1 immunotherapy in melanoma patients (Iraz et al, 2017;Gstalder et al, 2020). In addition, FBXW7 is strongly associated with tumor immune cell infiltration and immunotherapeutic responses in renal cell carcinoma(RCC) (Xing et al, 2022). NFAT1 is a member of the nuclear factor of activated T cell (NFAT) family, which is involved in many aspects of cancer, including carcinogenesis, cancer metastasis, formation of the tumor microenvironment, and immunotherapeutic response (Jiang et al, 2019).…”

FBXW7 in breast cancer: mechanism of action and therapeutic potential

“…A major cause of recurrence, metastasis and drug resistance in breast cancers lacking effective anti-hormonal targets is the formation of immunosuppression in the tumor microenvironment, and clinical breast cancer treatment strategies have shown great interest in single agent co-immunosuppressive therapy [ 110 ]. Crosstalk between FBXW7 and related binding proteins regulates immune cell numbers, metastasis, and the premetastatic niche, playing a role in breast cancer immunosuppression [ 111 , 112 ] (Fig. 5 F).…”