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. 2023 May 3;42(24):2007–2016. doi: 10.1038/s41388-023-02706-6

Fig. 6. Bid-mediated apoptosis is required for antitumor immunity induced by Everolimus.

Fig. 6

APCMin/+/BID−/− mice with established polyps on week 12 were treated with Everolimus for 3 days (A–G), or till week 48 (48 w). A Representative TUNEL IF in the polyps. Bar = 100 µm. B Quantitation of TUNEL+ cells in the polyps. C Representative c-Cas8 and p-eiF2α IF in the polyps. Bar = 100 µm. D Quantitation of indicated cells in the polyps. E Quantitation of Ly-6B.2+ cells and CD68+ cells in the polyps. F Survival. APCMin/+ mice were included as controls for BID KO mice. Log-rank test. ***P < 0.001, APCMin/+/BID-/- Ctrl vs. Ever, ****P < 0.0001 APCMin/+ vs. APCMin/+/BID−/−. G Quantitation of CD3+ and CD8+ cells in the polyps of indicated genotypes at 36 w (24 w treatment). B, D, E, G, n = 3 mice/group. ***P < 0.001, ****P < 0.0001 (Student’s T-Test, two-tailed). H Working model. Left, elevated Myc and mTOR maintain metabolic and immune adaptation in mutant APC-driven polyposis. mTOR inhibition breaks adaptation through Myc-dependent and -independent targets to induce immunogenic cell death required for long-term tumor control. Right, cell death is induced upon inhibition of p-4EBP1 and S6K1, leading to Myc reduction, AKT hyperactivation (p-AKT), ER stress (p-eIF2α/CHOP), and DR5-Cas8-tBid signaling.