Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review).

Cancer cells play a pivotal role in immune evasion by activating the programmed cell death protein 1 (PD‑1)/PD‑ligand (L)1 signaling pathway or immune cells within the tumor microenvironment. The ubiquitin‑proteasome system (UPS), the primary pathway for intracellular protein degradation, has been increasingly implicated in mediating tumor immune escape and resistance to anti‑PD‑1/PD‑L1 therapy. Targeting the UPS has demonstrated significant potential in improving the efficacy of tumor immunotherapy. Therefore, a deeper understanding of the molecular mechanisms by which UPS contributes to tumor resistance against PD‑1/PD‑L1 blockade, along with the optimization of UPS‑targeted small‑molecule drug design, holds scientific and clinical significance. In the present review, the role of UPS in tumor immune evasion through the regulation of PD‑1/PD‑L1 ubiquitination was discussed and potential therapeutic agents that may enhance the effectiveness of anti‑PD‑1/PD‑L1 treatment are summarized. These insights provide a theoretical foundation for advancing cancer immunotherapy and developing novel combination strategies.