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 IFN-γ and PD-L1, beyond their established roles in tumor-immune interactions, may contribute to the regulation of NSCLC 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 a putative autocrine TBX21/IL-4 signaling circuit that may sustain stem-like properties. PD-L1, in turn, is functionally integrated into plasticity-associated pathways involving the TGF-β signaling axis, β-catenin stabilization, epithelial-to-mesenchymal transition-associated microRNA networks, YAP/TAZ, CD44 and ATM signaling, as well as TRAF6/BECN1/NF-κB-dependent regulation of autophagy. Collectively, these findings support a role for IFN-γ and PD-L1 as context-dependent modulators of NSCLC plasticity, with potential implications for immunotherapy resistance, and provide a rationale for further exploring combinatorial treatment strategies and patient stratification approaches.