T‐cell exhaustion from a multiomics perspective: Differentiation mechanisms and regulatory networks in the journey from progenitor‐Exhausted T cells to terminally exhausted T cells

A central hurdle limiting the success of T-cell-based immunotherapies is the progressive dysfunction of T cells, known as exhaustion. Overcoming this exhausted state is therefore a pivotal objective in translational oncology and immunology. The advent of single-cell multiomics has fundamentally revised the once-prevailing view of exhaustion as a uniform endpoint. Instead, it is now recognised as a dynamic differentiation process comprising a spectrum of distinct cellular states. This spectrum is organised along a hierarchical axis, originating from progenitor-exhausted (Tpex) cells that retain proliferative potential and advancing towards terminally exhausted (Tex) populations with severely impaired effector functions. We undertake a comprehensive synthesis of multiomics data-spanning transcriptomic, epigenomic, metabolomic, proteomic and posttranslational modification (PTM)-proteomic layers-to decipher the interconnected regulatory programmes that dictate commitment along this exhaustion axis. From this integrated analysis, we derive a unified mechanistic framework that delineates the molecular drivers of Tpex cell fate determination and terminal exhaustion. Beyond its explanatory power for basic biology, this framework serves as a direct roadmap for therapeutic innovation, highlighting novel nodes for intervention aimed at reinvigorating the exhausted T-cell compartment. The practical application of these insights holds significant promise for enhancing the efficacy of established current immunotherapeutic platforms. KEY POINTS: This review is the first to integrate multi-omics evidence for constructing a dynamic regulatory map of T-cell exhaustion. It highlights the critical cross-omics synergistic mechanisms, such as metabolic reprogramming influencing epigenetic remodeling to drive cell fate. The multi-omics perspective presented directly informs novel therapeutic strategies.