Beyond immune surveillance: IFN-γ and PD-L1 as shapers of tumor plasticity in Non-Small Cell Lung Cancer (NSCLC)

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed the treatment of Non-Small Cell Lung Cancer (NSCLC), yet durable responses remain limited to a minority of patients. Tumor plasticity is increasingly recognized as a determinant of immunotherapy resistance, although the tumor-intrinsic contribution of immunomodulatory mediators such as IFN-γ and PD-L1 remains poorly understood. In this review, we examine emerging evidence that, beyond their established roles in tumor–immune interactions, IFN-γ and PD-L1 directly regulate NSCLC cell plasticity. IFN-γ can activate non-canonical programs involving dose-dependent ICAM1/PI3K/AKT/Notch1 signaling, BCAT1- and FGF2/β-catenin-mediated metabolic reprogramming, and autocrine TBX21/IL-4 signaling that sustains stem-like properties. PD-L1, in turn, modulates plasticity through crosstalk with the TGF-β/SOX2 axis, β-catenin stabilization, epithelial-mesenchymal transition-associated microRNA networks, YAP/TAZ, CD44 and ATM signaling, and TRAF6/BECN1/NF-κB-dependent regulation of autophagy. Collectively, these mechanisms position IFN-γ and PD-L1 as active regulators of NSCLC plasticity, with direct relevance to immunotherapy resistance, and point to novel avenues for combinatorial treatment strategies and patient stratification.