Cancers persist and progress despite the presence of tumor-infiltrating lymphocytes (TILs). A paradox of tumor immunology is that tumor antigen–specific TILs are dysfunctional in situ and yet can mediate regression of large metastatic tumors after immune checkpoint blockade or adoptive cell transfer. TILs are predominantly considered “exhausted” because of chronic antigen exposure, but recent studies have revealed that T cells within tumors exist in a continuum of epigenetic, transcriptional, and metabolic states. A small subset of T cell clonotypes in TILs expressing the transcription factor TCF7 possess stem cell–like behaviors including self-renewal, multipotency, and persistence. Although these cells appear to be responsible for tumor destruction in the setting of successful immunotherapy, the mechanisms underlying their generation and maintenance are unknown.

To progress from a naïve, stem cell–like state after activation, T cells rely on the uptake and consumption of extracellular nutrients to enact robust aerobic glycolysis and mTOR-driven anabolic growth. In multiple organisms, the cellular response to starvation preserves stemness and enhances organismal longevity. Cellular necrosis is a feature of many solid tumors, and higher densities of necrosis are inversely correlated to patient survival. Necrotic cells release intracellular contents into the extracellular space. Because the intracellular concentration of potassium is higher than the extracellular compartment (~145 mM versus ~5 mM), local potassium levels within the tumor interstitial space can exceed 40 mM. We hypothesized that elevated extracellular potassium found in tumor interstitial fluid would disrupt the electrochemical gradient that facilitates T cell nutrient uptake, simultaneously limiting the acquisition of effector programs and the coincident loss of stemness. In the present work, we sought to explore the impact of high levels of potassium found in tumors on T cell stemness and antitumor capacity.

We found that elevated extracellular potassium characteristic of the extracellular space within tumors reduced the uptake and consumption of local nutrients by antitumor T cells, inducing a state of functional caloric restriction. A starvation response ensued, resulting in autophagy, mitochondrially dominant metabolism, and a paucity of available cofactors obligatory for histone modification and the epigenetic remodeling required for progressive differentiation. Both nucleocytosolic acetyl–coenzyme A (CoA) and methionine intermediates were depleted. Depletion of nucleocytosolic acetyl-CoA limited the acquisition of histone acetylation on the promoters and enhancers of genes encoding effector molecules. Simultaneously, nutrient deprivation reduced methionine intermediates, depressing methylation of histone marks that normally suppress stemness-associated programs. Treatment of antitumor T cells with elevated extracellular potassium as well as pharmacologic or gene therapies mimicking mechanisms of functional starvation resulted in T cells with retained stemness, evidenced by self-renewal and multipotency, thereby enabling the enhanced destruction of large, established tumors.

These data provide a link between tumor-induced immune suppression and the stem cell–like properties of some antitumor T cells. Moreover, these findings deepen our understanding of how cancer can progress despite the presence of T cells that continue to harbor the capacity for its destruction. Finally, we identify new therapeutic strategies to metabolically induce stemness programs in antitumor T cells that enhance cancer immunotherapies …