Inactivating mutations in LKB1/STK11 are present in roughly 20% of nonsmall cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy. Unexpectedly, we found that LKB1 deficiency correlated with elevated tumor mutational burden (TMB) in NSCLCs from nonsmokers and genetically engineered mouse models, despite the frequent association between high-TMB and anti-PD-1 treatment efficacy. However, LKB1 deficiency also suppressed antigen processing and presentation, which are associated with compromised immunoproteasome activity and increased autophagic flux. Immunoproteasome activity and antigen presentation were restored by inhibiting autophagy through targeting the ATG1/ULK1 pathway. Accordingly, ULK1 inhibition synergized with PD-1 antibody blockade, provoking effector T-cell expansion and tumor regression in Lkb1-mutant tumor models. This study reveals an interplay between the immunoproteasome and autophagic catabolism in antigen processing and immune recognition, and proposes the therapeutic potential of dual ULK1 and PD-1 inhibition in LKB1-mutant NSCLC as a strategy to enhance antigen presentation and to promote antitumor immunity.

LKB1/STK11的失活突变存在于大约 20% 的非小细胞肺癌 (NSCLC) 中，预示着对抗 PD-1 免疫疗法的反应不佳。出乎意料的是，尽管高 TMB 和抗 PD-1 治疗效果之间经常存在关联，但我们发现LKB1缺乏与非吸烟者和基因工程小鼠模型的 NSCLC 中肿瘤突变负荷 (TMB) 升高相关。然而，LKB1缺乏也会抑制抗原加工和呈递，这与免疫蛋白酶体活性受损和自噬通量增加有关。通过靶向ATG1 / ULK1抑制自噬来恢复免疫蛋白酶体活性和抗原呈递途径。因此，ULK1 抑制与 PD-1 抗体阻断协同作用，在Lkb1突变肿瘤模型中引发效应 T 细胞扩增和肿瘤消退。本研究揭示了免疫蛋白酶体和自噬分解代谢在抗原加工和免疫识别中的相互作用，并提出了双重 ULK1 和 PD-1 抑制在LKB1突变 NSCLC 中作为增强抗原呈递和促进抗肿瘤免疫的策略的治疗潜力。