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T cell stemness and dysfunction in tumors are triggered by a common mechanism.

ABSTRACT: A paradox of tumor immunology is that tumor-infiltrating lymphocytes are dysfunctional in situ, yet are capable of stem cell-like behavior including self-renewal, expansion, and multipotency, resulting in the eradication of large metastatic tumors. We find that the overabundance of potassium in the tumor microenvironment underlies this dichotomy, triggering suppression of T cell effector function while preserving stemness. High levels of extracellular potassium constrain T cell effector programs by limiting nutrient uptake, thereby inducing autophagy and reduction of histone acetylation at effector and exhaustion loci, which in turn produces CD8⁺ T cells with improved in vivo persistence, multipotency, and tumor clearance. This mechanistic knowledge advances our understanding of T cell dysfunction and may lead to novel approaches that enable the development of enhanced T cell strategies for cancer immunotherapy.

SUBMITTER: Vodnala SK

PROVIDER: S-EPMC8194369 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Dysfunction and stemness of tumor-infiltrating T cells are triggered by a common mechanism

Project description:The paradox of tumor immunology is that tumor infiltrating lymphocytes (TILs) are dysfunctional in situ and yet are capable of stem cell-like behavior with self-renewal, massive expansion, multipotency, and eradication of large metastatic tumors. Here we report that the overabundance of potassium in the tumor microenvironment (TME) can explain both phenomena.

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