Unlocking T-cell plasticity in the tumor microenvironment: Insights into cancer immunotherapy and therapeutic innovations

T cells, the cornerstone of antitumor immunity, display remarkable heterogeneity and adaptability within the TME. As highlighted in the review by researchers from Fudan University Shanghai Cancer Center, T cells can transition between effector, exhausted, and regulatory states in response to cues from tumor cells, immune cells, and metabolic stressors in the TME. For instance, CD8+ T cells can differentiate into progenitor exhausted (T_PEX), effector (T_EFF), or terminally exhausted (T_TEX) subsets, with distinct cytotoxicity and antigen responsiveness . Meanwhile, CD4+ T cells, including Th1 (antitumor) and Tregs (pro-tumor), exhibit bidirectional roles in shaping immune responses.

Spatial organization within the TME further influences T-cell function. T cells in the tumor core face immunosuppressive cues like hypoxia and inhibitory receptors, while those at the invasive margin show enhanced activation and correlate with better therapeutic outcomes . Tertiary lymphoid structures (TLSs), enriched in T cells and dendritic cells, emerge as critical hubs for antitumor immunity, with their presence linked to improved survival across solid tumors.

The review emphasizes three key regulatory layers of T-cell plasticity: cellular signals including direct cell-to-cell interactions and soluble factors like cytokines and chemokines that dictate T-cell activation or exhaustion; metabolic reprogramming where tumor-induced stress such as glucose depletion and lipid peroxidation impairs T-cell function while certain fatty acids support mitochondrial function; and physical and biological factors like extracellular matrix (ECM) stiffness, reactive oxygen species (ROS) with dual effects on T-cell activation and exhaustion, and the intratumoral microbiome modulating T-cell activity. 

In terms of therapeutic strategies, the review outlines innovative approaches such as immune checkpoint therapy with combinations of PD-1 inhibitors and TGF-β blockers or bispecific antibodies, metabolic modulation targeting glucose or lipid metabolism to restore T-cell function, adoptive cell therapy with genetically engineered CAR-T cells having enhanced metabolic fitness, and spatial reprogramming by disrupting ECM barriers or enhancing TLS formation. The authors note challenges like tumor heterogeneity and off-target toxicity while emphasizing the need for spatial omics and single-cell technologies to decode T-cell dynamics for personalized therapies.

 

See the article:

Unlocking T‐Cell Plasticity in the Tumor Microenvironment: Implications for Cancer Progression and Therapeutic Strategies

https://doi.org/10.1002/mog2.70023

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