TSC2 regulates tumor susceptibility to TRAIL‐mediated T‐cell killing by orchestrating mTOR signaling

Abstract Resistance to cancer immunotherapy continues to impair common clinical benefit. Here, we use whole‐genome CRISPR‐Cas9 knockout data to uncover an important role for Tuberous Sclerosis Complex 2 (TSC2) in determining tumor susceptibility to cytotoxic T lymphocyte (CTL) killing in human melanoma cells. TSC2‐depleted tumor cells had disrupted mTOR regulation following CTL attack, which was associated with enhanced cell death. Wild‐type tumor cells adapted to CTL attack by shifting their mTOR signaling balance toward increased mTORC2 activity, circumventing apoptosis, and necroptosis. TSC2 ablation strongly augmented tumor cell sensitivity to CTL attack in vitro and in vivo , suggesting one of its functions is to critically protect tumor cells. Mechanistically, TSC2 inactivation caused elevation of TRAIL receptor expression, cooperating with mTORC1‐S6 signaling to induce tumor cell death. Clinically, we found a negative correlation between TSC2 expression and TRAIL signaling in TCGA patient cohorts. Moreover, a lower TSC2 immune response signature was observed in melanomas from patients responding to immune checkpoint blockade. Our study uncovers a pivotal role for TSC2 in the cancer immune response by governing crosstalk between TSC2‐mTOR and TRAIL signaling, aiding future therapeutic exploration of this pathway in immuno‐oncology.