Lactate-Induced PPP1R1B Upregulation Drives Resistance to Neoadjuvant Immunotherapy in NSCLC via IRF3...

Neoadjuvant immunotherapy has improved clinical outcomes in resectable non-small cell lung cancer (NSCLC); however, a substantial proportion of patients fail to achieve durable responses, and the mechanisms underlying therapeutic resistance remain incompletely understood. Here, we identified protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B) as a metabolic driver of immunotherapy resistance in NSCLC through RNA sequencing of tumors with differential responses to neoadjuvant anti-PD-1 therapy. PPP1R1B was significantly upregulated in non-responders and correlated with poor prognosis in NSCLC patients. Mechanistically, PPP1R1B directly interacted with IRF3 through the Arg29 residue and promoted dephosphorylation of IRF3 at Ser396, thereby suppressing IRF3 activation and downstream interferon-β (IFN-β) signaling. PPP1R1B-mediated inhibition of IFN-β signaling reduced CD8⁺ T-cell infiltration and impaired antitumor immunity, ultimately conferring resistance to anti-PD-1 therapy in vivo. Blockade of IFN-β signaling abrogated the antitumor effects induced by PPP1R1B depletion, supporting an immune-dependent mechanism. Notably, tumors resistant to neoadjuvant immunotherapy exhibited impaired oxidative phosphorylation and excessive lactate accumulation. Lactate induced PPP1R1B expression through NF-κB-dependent transcriptional activation, linking metabolic reprogramming to innate immune suppression. Collectively, our findings identify a lactate/NF-κB/PPP1R1B/IRF3 signaling axis that drives immune evasion and resistance to neoadjuvant immunotherapy in NSCLC, and nominate PPP1R1B as a potential biomarker and therapeutic target for overcoming anti-PD-1 resistance.