Persistent IFN-γ signaling in acquired resistance to PD-(L)1 blockade in NSCLC

Immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1 have transformed the therapeutic landscape of non-small cell lung cancer (NSCLC), producing durable responses in a subset of patients. Yet for most, clinical benefit is undermined by the development of acquired resistance (AR), a phenomenon that continues to limit the long-term success of immunotherapy. Recent analyses have drawn attention to persistent interferon-γ (IFN-γ) signaling as a paradoxical hallmark of AR: a cytokine typically associated with effective antitumor immunity that, when chronically engaged, sustains immune dysfunction. Notably, Memon et al.^[1] distinguished two resistance states - “IFN-γ-increased” and “IFN-γ-stable” - each characterized by sustained inflammatory signatures despite clinical progression. In this commentary, we synthesize existing literature to expand upon this model. We review molecular and cellular mechanisms by which chronic IFN-γ drives resistance through the STAT1/IRF1 axis, epigenetic stabilization of exhaustion, antigen-presentation loss, and metabolic suppression. We extend the discussion to innate immunity, bystander T-cell responses, and stromal regulation, emphasizing spatial heterogeneity as a critical mediator of IFN-γ biology. Finally, we explore translational strategies - including rational checkpoint combinations, radiotherapy–immunotherapy sequencing, epigenetic modulation, and innate immune engagement - that may reprogram IFN-γ–permissive resistance states. We argue that IFN-γ persistence should not be viewed as an isolated mechanism but as a central hub in a broader resistance network, and we propose a phenotype-guided framework for therapeutic intervention in AR NSCLC.