FBXO38 is an F-box protein serving as a substrate recognition component of SCF E3 ubiquitin ligase complexes 1. Its primary characterized function involves mediating Lys48-linked polyubiquitination and proteasomal degradation of PD-1 in activated T cells, thereby enhancing anti-tumor immunity 1. FBXO38-deficient T cells display elevated PD-1 levels and accelerated tumor progression in mice, which can be reversed by anti-PD-1 therapy 1. Notably, FBXO38 expression is transcriptionally downregulated in tumor-infiltrating T cells, though IL-2 therapy can restore expression 1. Beyond T cell immunity, FBXO38 promotes macrophage immunosuppressive M2-like polarization via MAPK and IRF4 signaling; its deletion in macrophages blocks tumor development and protects against colitis 2. FBXO38 also stabilizes KIF20B independent of SCF complexes to regulate cytokinesis 3. Additionally, FBXO38 regulates PD-1 phosphorylation-dependent stability; phosphorylated PD-1 escapes FBXO38-mediated degradation 4. Disease relevance includes autosomal dominant hereditary distal motor neuronopathy (HMN6), reflecting FBXO38's neuromuscular functions. Recent evidence indicates FBXO38's role in PD-1 regulation remains contested, warranting further investigation.