DSTYK inhibition sensitizes lung cancer cells to immunotherapy. (A) Parental and KO LLC tumor–bearing mice were treated with or without anti–PD-1. Statistical analysis was performed by ANOVA. Parental vs. KO, P = 0.05; parental vs. KO + anti–PD-1, P = 0.008. No differences between parental and parental + anti–PD-1 treated mice. Number of C57BL/6J mice per group = 7. (B) Kaplan–Meier plot showing PFS of lung cancer patients treated with immunotherapy and classified by the presence of absence of DSTYK amplification (n = 76). Log-rank test, P = 0.06. (C) Proposed model of DSTYK molecular mechanism in lung cancer cells. (1) DSTYK inhibits mTOR activity; (2) mTOR mediates TFEB/3 phosphorylation preventing its nuclear translocation; (3) TFEB/3 transcribe genes related to lysosomal biogenesis and maturation; (4) DSTYK binds P62, which is involved in the NRF2/KEAP1 pathway; (5) DSTYK protects mitochondrial integrity; (6) autophagy prevents TNF-α mediated apoptosis. *, P < 0.05; **, P < 0.01.