The ZFP36 Family as a Post-Transcriptional Immune Checkpoint in Immunity and Disease: Molecular Mechanisms and Functional Implications.

The zinc finger protein 36 (ZFP36) family, including ZFP36/tristetraprolin (TTP), ZFP36 CCCH-type-like 1 (ZFP36L1), and ZFP36 CCCH-type-like 2 (ZFP36L2), consists of conserved CCCH-type tandem zinc-finger RNA-binding proteins. These proteins recognize AU-rich elements (AREs) in target mRNAs and promote deadenylation, decay, and translational repression. In this review, we use the term post-transcriptional immune checkpoint in a restricted conceptual sense: ZFP36 family proteins are intracellular, RNA-level negative regulators that tune the magnitude, duration, and resolution of immune effector programs, rather than classical receptor-ligand immune checkpoints such as programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). We summarize structural features, ARE-recognition mechanisms, mRNA decay pathways, translational repression mechanisms, and post-translational regulation of the ZFP36 family, while explicitly distinguishing mechanisms established for ZFP36 from those inferred for ZFP36L1 and ZFP36L2. We then review cell-type-specific roles in innate and adaptive immunity, including myeloid inflammatory responses, barrier tissue inflammation, innate lymphoid cell function, T cell activation and effector differentiation, regulatory T cell stability, B cell development, and antiviral immunity. In cancer, ZFP36 family members show context-dependent functions that should be separated into tumor-cell-intrinsic effects and immune-microenvironment-dependent effects. They suppress tumor progression by destabilizing pro-inflammatory, angiogenic, metabolic, and epithelial-mesenchymal transition (EMT)-associated transcripts, yet may also restrict antitumor immune responses or promote immune evasion in selected tumor contexts. Finally, we discuss autoimmune and inflammatory diseases, allergic disorders, transplant immunity, neuroimmune relevance, and therapeutic strategies, emphasizing the current evidentiary limits, preclinical status, and safety concerns of ZFP36 family modulation.