# 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

## TL;DR

This paper reviews how T cells become exhausted in cancer, using multiomics data to map the process and suggest new therapies.

## Contribution

The first comprehensive integration of multiomics data to construct a regulatory map of T-cell exhaustion.

## Key findings

- Persistent antigen exposure drives Tpex to Tex differentiation through a hierarchical exhaustion axis.
- Multiomics regulation involves coordinated networks across transcriptomic, epigenomic, and metabolic layers.
- Therapeutic strategies targeting exhaustion networks include ICB, epigenetic drugs, and engineered 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.

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.

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.

(1) Core Process: Persistent antigen, from TDLNs to TME, drives Tpex → Tex‐int → Tex‐term differentiation. (2) Multiomics Regulation: This fate transition is orchestrated by a co‐ordinated, multi‐layered molecular network. (3) Functional Outcome: Dysregulated signalling and surging co‐inhibitory receptors lock in proliferative arrest and functional loss. (4) Therapeutic Strategies: Rational combinations (ICB, epigenetic drugs, engineered T cells) target this network.