Targeting NHEJ activates STING signaling through MYC degradation to boost antitumor immunity in SCLC.

Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Paradoxically, this tumor displays a high mutation burden; however, a modest response to immunotherapy. Improving Immunotherapy response in SCLC patients remains an unmet need. Here, we report that across 24 tumor types, including over 179,000 real-world patient tumors, SCLC has the highest expression of nonhomologous end joining (NHEJ) DNA repair regulator PRKDC (DNAPKcs). High PRKDC expression predicts poor response to immunotherapy in SCLC. DNAPKcs depletion causes activation of cGAS/STING pathway due to cytoplasmic accumulation of double-stranded DNA, inducing immunogenicity and enhancing sensitivity of SCLC models to immunotherapy. Analyses in SCLC cell lines and mouse models shows that depletion of DNAPKcs leads to proteasomal degradation of MYC via GSK3β pathway. We show that DNAPKcs upregulation contributes to immunotherapy resistance and DNAPKcs inhibition represents a promising therapeutic strategy to induce antitumor immunity and potentiate immunotherapy efficacy in immunologically suppressed SCLC.