Roles of RNA-binding proteins in macrophage function regulation and immunotherapy

Chunhong Li^1*Xiulin Jiang^2,3*Chongxin Li⁴Yixiao Yuan³Qiang Zhou¹Qiang Wang^1*

• ¹Suining Central Hospital, Suining, China
• ²Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, United States
• ³City of Hope, Duarte, United States
• ⁴Kunming Medical University Affiliated Qujing Hospital, Qujing, China

Macrophages are essential components of the innate immune system and exhibit remarkable functional plasticity, playing pivotal roles in inflammatory responses, maintenance of tissue homeostasis, and the initiation and progression of tumors as well as a wide range of other diseases. Accumulating evidence in recent years has demonstrated that, in addition to classical transcriptional regulation, post-transcriptional regulation is equally critical for macrophage fate determination and functional specialization. RNA-binding proteins (RBPs), as central regulators of post-transcriptional gene control, orchestrate a sophisticated and dynamic gene expression network by modulating RNA splicing, nucleocytoplasmic transport, stability and decay, translational efficiency, RNA epigenetic modifications, liquid–liquid phase separation, and chromatin-associated processes. Substantial experimental data indicate that RBPs are deeply involved in macrophage polarization, survival and programmed cell death, as well as metabolic reprogramming, thereby shaping the magnitude of inflammatory responses, immune suppressive states, and remodeling of the tumor microenvironment. In this review, we systematically summarize the molecular mechanisms by which RBPs regulate macrophage functions, with particular emphasis on their roles in inflammatory disorders, cancer, and metabolism-related diseases. We also highlight recent advances in the coordinated regulation of macrophage biology by RBPs in conjunction with RNA modifications, including m⁶A, m⁵C, and ac⁴C, as well as noncoding RNAs. Finally, we discuss the opportunities and challenges of targeting RBPs as emerging immunotherapeutic strategies, underscoring their potential in reprogramming the tumor immune microenvironment and enhancing the efficacy of immunotherapy, thereby providing a theoretical framework for the development of precise immune intervention approaches.