RNA-binding motif proteins as context-dependent regulators of tumor–immune crosstalk, genome stability, and therapeutic vulnerabilities in cancer

Cancer progression relies on dynamic post-transcriptional RNA regulation to enable phenotypic plasticity, immune evasion, and therapeutic resistance. RNA-binding motif (RBM) proteins emerge as pivotal orchestrators of these processes, modulating splicing, mRNA stability, and translation in a context-dependent manner across malignancies. This article provides a narrative mechanistic synthesis of published evidence and does not report original cohort construction or predictive-model development. Here, we review how RBM-driven RNA programs promote proliferative advantages through splicing rewiring, transcript stabilization via m6A modifications, and dual oncogenic/tumor-suppressive roles. We highlight RBM contributions to epithelial-mesenchymal transitions (EMT) and metastatic niche adaptation, including isoform-specific regulation of EMT effectors and metabolic reprogramming. Furthermore, RBMs shape tumor-immune dynamics by triggering innate immune activation through RNA misprocessing, suppressing adaptive immunity through PD-L1 upregulation, and remodeling the immunosuppressive microenvironment via cytokine and metabolic circuits. RBMs also integrate RNA processing with the choice of DNA repair pathways and genotoxic stress responses, underpinning resistance to chemotherapy and radiotherapy. Finally, pharmacological targeting of RBMs, such as RBM39 degradation via molecular glues like indisulam, exploits splicing dependencies to collapse oncogenic states and overcome resistance. These insights position RBMs as therapeutic nodes for precision immuno-oncology, with implications for biomarker-driven strategies in splicing-addicted tumors.