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New Discovery in Nature: A signaling pathway reverses T-cell exhaustion, enabling a “precision breakthrough” in cancer immunotherapy!

　　T cell exhaustion is a dysfunctional state that arises under the prolonged influence of chronic infection or the tumor microenvironment, characterized by the loss of effector functions and the sustained high expression of inhibitory receptors (such as PD-1 and TIM-3). Based on functional heterogeneity, exhausted T cells can be classified into progenitor-like exhausted T cells (Tₚᵣₒ₉) and terminally exhausted T cells (Tₜₑₓ); among these, Tₜₑₓ cells exhibit virtually no response to immunotherapy and represent the primary cause of treatment failure in clinical settings.

　　Previous studies have largely relied on transcriptomic sequencing, yet the correlation between mRNA levels and protein expression is extremely low (Pearson correlation coefficients of only 0.31–0.38). This pathway‑specific discordance in expression is particularly pronounced in key regulatory pathways such as metabolic control and epigenetic modification—for example, changes in mRNA levels within metabolic pathways like glycolysis and oxidative phosphorylation scarcely reflect the true dynamics of protein abundance. As the direct executors of cellular functions, proteins are subject to post‑transcriptional regulatory processes—including translation efficiency, post‑translational modifications, and degradation rates—that constitute critical nodes in the regulation of T‑cell function. Consequently, elucidating the proteomic signatures of T‑cell exhaustion has emerged as a central strategy for overcoming the limitations of existing research.

　　

 

　　In October 2025, a team from The Ohio State University published a groundbreaking study in Nature titled “Proteotoxic stress response drives T cell exhaustion and immune evasion.” Through systematic proteomic analysis, the researchers for the first time elucidated the molecular mechanisms by which the proteotoxic stress response (PSR, also referred to as Tex‑PSR) drives T‑cell exhaustion, thereby providing a novel theoretical foundation and therapeutic targets for overcoming resistance to immunotherapy.

　　I. Key Findings: The Tₑₓ-PSR Pathway—A Driver of T Cell Exhaustion

　　The research team established a cross‑model, dynamic proteomic atlas of T‑cell exhaustion using the lymphocytic choriomeningitis virus (LCMV) infection model, the MC38 colon tumor model, the MB49 bladder tumor model, and an in vitro T‑cell culture system, thereby identifying a novel, specific mechanism—Tₑₓ‑PSR.

　　

 

　　Figure 1: PSR is activated in exhausted T cells, accompanied by the dynamic expression of chaperone proteins.

　　| Core Features of Tₑₓ-PSR

　　Unlike the classical stress response, in which protein synthesis is suppressed, Tₑₓ-PSR exhibits distinct pathological features:

　　Enhanced global protein translation activity:

　　HPG (methionine analog) incorporation assays confirmed that the protein synthesis rate in Tₜₑₓ cells is significantly higher than that in effector T cells (Tₑff), and this phenomenon was also observed in tumor-infiltrating T cells (TILs).

　　Accumulation of protein aggregates:

　　Using NIAD‑4 and CRANAD‑2 fluorescence staining combined with mass spectrometry, we found that in Tₜₑₓ cells, 74% of proteins (3,889 distinct proteins) transition from low‑molecular‑weight forms to high‑molecular‑weight aggregates; the aggregation of effector molecules such as granzyme B and perforin results in the loss of their functional activity.

　　Increased formation of stress granules (SGs):

　　The frequency of G3BP1-positive stress granules is significantly increased in Tₜₑₓ cells, and knockdown of G3BP1 partially restores cytokine secretion.

　　Selective upregulation of chaperone proteins:

　　Endoplasmic reticulum chaperone proteins such as BiP (encoded by Hspa5), gp96 (encoded by Hsp90b1), and ERO1A are highly upregulated, whereas the expression of basic folding machinery components, including the TRiC complex, is downregulated, resulting in a pathological imbalance in protein folding.

　　| Causal relationship verification: Protein misfolding directly induces depletion

　　To establish the causal relationship between proteostasis disruption and T-cell exhaustion, the research team designed two sets of pivotal experiments:

　　01 Chemical Induction Experiment:

　　Induction of protein misfolding with the proline analog AZC, even in the absence of chronic antigenic stimulation, drives T effector cells to acquire a PD1⁺TIM3⁺ exhaustion phenotype, accompanied by diminished cytokine‑secretion capacity and reduced tumor‑infiltrating ability in the B16‑OVA tumor model.

　　02 Gene Induction Experiment:

　　By retroviral transduction of a folding-deficient CFTR mutant (ΔF508), a canonical exhaustion phenotype can be induced in both human and murine CD8⁺ T cells, demonstrating that protein misfolding alone is sufficient to initiate the T cell exhaustion program.

　　

 

　　Figure 2: Protein misfolding can promote T-cell exhaustion.

　　II. Regulatory Mechanism: The Central Regulatory Role of the AKT Signaling Pathway

　　Through proteomic analysis of key signaling pathways, the research team identified the AKT pathway as the upstream regulatory hub of Tₑₓ-PSR:

　　Persistent AKT activation: Phosphorylated AKT at the Ser473 site is markedly elevated in Tₜₑₓ cells and remains sustained in tumor-infiltrating T cells.

　　Specific inhibitory effects: At low doses, the AKT inhibitor MK2206 (0.2 μM and 1 μM) significantly reduces the rate of protein synthesis, decreases protein aggregation, and downregulates gp96 expression, while simultaneously restoring T‑cell effector functions and the SLAMF6⁺TIM3⁻ phenotype, without affecting cell proliferation or survival.

　　Activator validation: Constitutively activated myrAKT, when forcibly expressed in naïve T cells, can directly induce Tₑₓ‑PSR–specific features and a terminally exhausted phenotype, resulting in the loss of antitumor activity in the B16‑OVA tumor model.

　　Pathway specificity: The PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin did not significantly ameliorate T-cell exhaustion, thereby confirming the specificity of the AKT pathway in the regulation of Tₑₓ-PSR.

　　

 

　　Figure 3. Sustained AKT signaling induces Tₑₓ-PSR.

　　III. Clinical Translational Value: Breakthroughs from Mechanisms to Therapeutic Strategies

　　1. Therapeutic Potential of Targeting the Tₑₓ-PSR Chaperone Protein

　　Using CRISPR-Cas9 gene-editing technology, the research team demonstrated that knocking out Hspa5 (BiP), Hsp90b1 (gp96), or Ero1a significantly ameliorates the T-cell exhaustion phenotype:

　　Enhanced effector functions: Knockout of the cells significantly increases their capacity to secrete IFNγ and TNF, while downregulating the expression of TIM3 and CD39.

　　Enhanced in vivo antitumor activity: In the MB49‑gp33 tumor model, gene‑edited P14 T cells significantly inhibited tumor growth, prolonged mouse survival, and increased the proportions of cytotoxic CX3CR1⁺ and stem‑cell‑like TCF1⁺ subsets among tumor‑infiltrating lymphocytes.

　　In vivo validation: In a chronic LCMV Clone 13 infection model, CD8⁺ T cell–specific Hsp90b1 knockout mice exhibited a marked expansion of antigen‑specific CD8⁺ T cells, an increased proportion of Tₚᵣₒ₉ cells, and reduced expression of exhaustion markers.

　　2. Tₑₓ-PSR as a biomarker for clinical prognosis and treatment response prediction

　　Analysis of single-cell transcriptomes from 17 human tumor types reveals:

　　① Tₑₓ-PSR features are highly enriched in human Tₜₑₓ cells and are positively correlated with the degree of T-cell exhaustion;

　　② Among patients with hepatocellular carcinoma, a higher Tₑₓ-PSR score in CD8⁺ T cells is associated with shorter overall survival and can serve as an independent prognostic indicator.

　　③ Among patients with diffuse large B-cell lymphoma receiving anti‑CD19 CAR‑T therapy, and those with non‑small cell lung cancer and renal cell carcinoma undergoing anti‑PD1 treatment, the Tₑₓ‑PSR scores of non‑responders were significantly higher than those of responders, providing a molecular biomarker for the precise clinical identification of patients who are likely to benefit.

　　

 

　　3. The potential of combination therapy through repurposing old drugs

　　Research has shown that ganetespib, an HSP90 inhibitor already in clinical trials, can significantly enhance the efficacy of immune checkpoint inhibitors by inhibiting gp96 activity. This finding provides a theoretical basis for the combination‑therapy strategy of “AKT inhibitor/Tₑₓ‑PSR chaperone inhibitor plus immune checkpoint inhibitor,” offering a new avenue for optimizing existing treatment regimens.

　　IV. Significance of the Study and Future Directions

　　This study, through systematic proteomic analysis, has for the first time elucidated the central driving role of protein homeostasis disruption in T‑cell exhaustion, thereby challenging the traditional paradigm dominated by transcriptomic research. Its scientific significance is manifested on three levels:

　　1. Mechanistic innovation: This study elucidates a novel exhaustion‑driven pathway, Tₑₓ‑PSR, and establishes a comprehensive regulatory cascade: “AKT activation → aberrant protein synthesis → accumulation of misfolded proteins → T cell exhaustion.”

　　2. Technological breakthrough: It has demonstrated the irreplaceable role of proteomics in elucidating cellular functional regulation, thereby establishing a new paradigm for studying immune cell functions.

　　3. Clinical Translation: Identified druggable targets such as BiP, gp96, and AKT, and developed the Tₑₓ-PSR scoring system, providing critical support for the precision and combination approaches in immunotherapy.

　　Future research should further elucidate the molecular mechanisms by which T cells sense protein aggregation, optimize drug‑delivery systems targeting Tₑₓ‑PSR, and conduct clinical trials evaluating the combination of AKT inhibitors or HSP90 inhibitors with immunotherapy, which holds promise for developing novel therapeutic strategies to overcome resistance to immunotherapy.

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