TIM ‐3 Functions as an Activator of NK Cells in GBM and Can Be Upregulated by Torin‐1: Implications for Exogenous

ABSTRACT

Functional dysregulation in the microenvironment of glioblastoma (GBM) fuels tumour cell proliferation at the expense of negatively reprogramming natural killer (NK) immunosurveillance. Building on our previous findings that tumour‐infiltrating NK cells from GBM patients downregulate TIM‐3 and that TIM‐3 loss correlates with reduced cytotoxic potential, we sought to further investigate TIM‐3 as a marker of functional NK cell activity. Here, we demonstrate that Torin‐1, a pharmacological inhibitor of mTOR, upregulates TIM‐3 expression on NK cells, sparing and enriching this functionally competent population while simultaneously suppressing GBM metabolism. Using patient data, genetic knockout models, and patient‐derived orthotopic xenografts, we characterize TIM‐3 as a receptor that contributes to NK cell activation and enables retention of effector function under conditions of torin1 therapy. These findings have direct implications for exogenous NK cell transplantation strategies, suggesting that TIM‐3 expression status should be considered in the selection and engineering of NK cell products for adoptive transfer into GBM, and that Torin‐1 preconditioning may enhance the functional competence of transplanted NK cells within the tumour microenvironment.