From Translation Milestones to Clinical Breakthroughs: Decision-Making Hubs and Translational Strategies for RNA-Binding Proteins in the Immunotherapy of Haematological Malignancies.
TL;DR
This review introduces 'translational checkpoints' as a synthesized working framework for overcoming resistance by targeting RNA-binding proteins (RBPs) that govern rapid protein synthesis in tumour and immune cells and establishes a four-subtype diagnostic stratification system and five actionable therapeutic strategies.
Abstract
Immunotherapy for haematological malignancies-including CAR-T and immune checkpoint inhibitors-is limited by resistance driven by rapid adaptive changes at the tumour-immune interface that transcriptional regulation cannot address. This review introduces 'translational checkpoints' as a synthesized working framework for overcoming resistance by targeting RNA-binding proteins (RBPs) that govern rapid protein synthesis in tumour and immune cells. We address three core questions: how tumours evade immune surveillance, how immune dysfunction arises, and how to develop targeted interventions. We cover the molecular basis of translational checkpoints, tumour-intrinsic checkpoints (IGF2BP-mediated antigen silencing, CSDE1-driven neutralisation of innate immunity, RNF220/FXR1-mediated metabolic remodelling, and the csNPM1 cell-surface checkpoint), immune cell-intrinsic checkpoints (haematopoietic stem cell fate regulation, LARP4-driven T-cell exhaustion, and the dual role of YTHDF2 in B-cell transformation), and RNA modification-RBP networks. Based on the 'RBP-mediated bidirectional checkpoint model', we establish a four-subtype diagnostic stratification system and propose five actionable therapeutic strategies-including LARP4 gene-edited CAR-T, YTHDF2 inhibitors plus CAR-T, and csNPM1-targeting antibodies. All recommendations are annotated with evidence strength, and timelines are speculative, conditional on preclinical-to-clinical progression. This framework provides a practical roadmap for patient stratification and precision immunotherapy. The 'translational checkpoint' is a synthesized conceptual framework from aggregated preclinical data, not an established nomenclature. Key knowledge gaps remain: RBP redundancy, context-dependent dual functions of YTHDF2 and CSDE1, and cell-type-specific effects in primary human haematopoietic tissue.
