Targeting alpha-ketoglutarate starvation within the tumor-immune microenvironment rescues T cell effector function in cancer immunotherapy

Calcium-aKG supplementation elevates intratumoral alpha-ketoglutarate and significantly increases immunotherapy effectiveness in mouse models of NSCLC.

• Why it matters: Chronic antigen stimulation and hypoxia in the tumor-immune microenvironment drive T cell exhaustion and loss of effector function, linked to metabolic inflexibility and repressive epigenetic remodeling.
• What they did: In vitro, chronic antigen stimulation and hypoxia suppress intracellular alpha-ketoglutarate, and cell-permeable aKG supplementation rescues effector cytokine production and cytotoxic capacity while restoring H3K27 demethylase activity (UTX, JMJD3).
• The result: In vivo, dietary calcium-aKG raises serum and intratumoral aKG and improves immunotherapy effectiveness in NSCLC mice; in NSCLC patients, older (>65 years) individuals show decreased serum aKG and serum aKG levels are associated with poor immunotherapy response.