A recent study in Nature Communications and supporting experimental research has spotlighted Ant2, a mitochondrial transporter protein, as a target for dramatically amplifying T cell anti-tumor activity. The key insight is that Ant2 orchestrates the way T cells generate and consume energy within their mitochondria, influencing the “metabolic fitness” necessary for sustained immune attack.

Ant2 (adenine nucleotide translocase 2) plays a significant role in prostate cancer progression and therapy resistance. It is highly overexpressed in prostate cancer tissues compared to normal prostate tissue, with expression levels up to four-fold higher in tumor samples. Silencing or inhibiting Ant2 in prostate cancer models suppresses cell growth, induces apoptosis, and increases sensitivity to pro-apoptotic agents such as TRAIL. Ant2 activity is further regulated by specific microRNAs and post-translational modifications like phosphorylation and acetylation, and its role in cell metabolism and apoptosis has made it an attractive emerging therapeutic target in prostate cancer research.

Researchers generated T cell-specific Ant2 knockout mice and found that this loss not only rewired T cell metabolism—increasing mitochondrial biogenesis and anabolic processes—but led to an activated-like state enhancing the cells’ effector capabilities. Metabolically, Ant2-deficient T cells bypassed the usual need for energy reprogramming at activation, instead manifesting heightened proliferation and cytotoxicity versus controls.

Additionally, small-molecule inhibition of Ant2 recapitulated these phenotypes in wild-type T cells. Treated cells exhibited superior proliferation, cytokine secretion, and tumor cell killing in diverse in vivo cancer models, underscoring the translational potential for drug-based T cell metabolic rewiring in immunotherapy.

Source.