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

Resistance to cancer immunotherapy continues to impair common clinical benefit. Here, we uncover an important role for Tuberous Sclerosis Complex 2 (TSC2) in determining tumor susceptibility to cytotoxic T lymphocytes (CTL) killing, both in vitro and in vivo. TSC2-depleted tumor cells showed disrupted mTOR regulation upon CTL attack, which was associated with enhanced cell death. Tumor cells adapted to CTL attack by shifting their mTOR signaling balance toward increased mTORC2 activity to circumvent apoptosis and necroptosis. TSC2 critically protected tumor cells as its ablation strongly augmented tumor cell sensitivity to CTL attack. Mechanistically, TSC2 inactivation caused elevation of TRAIL receptors 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 blockades. 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.