Pellino ubiquitin ligases: double-edged swords in hematologic malignancies-from oncogenic stabilizers to therapeutic vulnerabilities.

The Pellino protein family is an evolutionarily conserved group of E3 ubiquitin ligases comprising Pellino1, Pellino2, and Pellino3. This family plays a central role in modulating inflammatory responses and immune signaling pathways through substrate ubiquitination. Recent studies have revealed that the Pellino family performs a unique dual regulatory function within the immune microenvironment of hematological malignancies. On the one hand, it contributes to tumor progression by promoting an immunosuppressive environment, such as enhancing the function of myeloid-derived suppressor cells (MDSCs) and increasing tumor cell drug resistance. On the other hand, it exhibits tumor-suppressive properties by activating antitumor immune responses, including the regulation of CD8⁺T-cell effector functions and the enhancement of NK cell cytotoxicity. The underlying molecular mechanisms involve bidirectional regulation of multiple signaling pathways, such as the Toll-like receptor, IL-1R, T-cell receptor, and nonclassical nuclear factor kappa B(NF-κB) pathways, thereby dynamically balancing the immune status within the tumor microenvironment. Clinical studies have demonstrated that the expression levels of Pellino family members are closely associated with the diagnosis, classification, and prognosis of hematological tumors, indicating their potential as biomarkers. Moreover, targeted intervention strategies based on their E3 ubiquitin ligase activity may offer novel approaches to increase the efficacy of immunotherapies. This review summarizes the structural and functional characteristics of the Pellino protein family, its dual regulatory mechanisms in the immune microenvironment of hematological tumors, and recent advances in clinical translation, aiming to provide a theoretical foundation for further understanding its biological roles and promoting targeted therapeutic research.