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

Abstract 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.