Tumor-intrinsic IRE1alpha signaling drives immune evasion and resistance to immune checkpoint inhibitor in lung cancer by upregulating PD-L1 and remodeling the tumor microenvironment

Tumor cells exploit endoplasmic reticulum (ER) stress pathways for survival. While the role of the unfolded protein response in tumorigenesis is well-established, its specific effect on the tumor microenvironment (TME) and therapeutic resistance in non-small cell lung cancer (NSCLC), particularly via IRE1alpha signaling, remains poorly understood. Here, we demonstrate that high IRE1alpha activity correlates with poor prognosis and resistance to immune checkpoint inhibitors in NSCLC patients. IRE1alpha activation was associated with an immunosuppressive TME, characterized by enriched regulatory T-cell (Treg) and M2-like tumor-associated macrophage (TAM) signatures in patient cohorts. Consistently, genetic ablation of tumor-intrinsic IRE1alpha ( ERN1 KO) in immunocompetent mice significantly attenuated tumor growth and enhanced CD8+ T-cell infiltration. Mechanistically, IRE1alpha promoted the expression and secretion of key chemokines, specifically CCL20, which in turn drove M2-like macrophage differentiation in vitro. Notably, this pro-tumorigenic secretome was abrogated by the IRE1alpha inhibitor MKC8866. Concurrently, IRE1alpha-XBP1s signaling synergized with IFNgamma to directly upregulate tumor-intrinsic PD-L1 expression. This process was mediated by the activation of the RIG-I-IRF1 axis, sustained STAT1 phosphorylation, and direct XBP1s binding to the CD274 promoter. Collectively, tumor-intrinsic IRE1alpha orchestrates immune evasion in NSCLC by amplifying tumor-intrinsic PD-L1 expression through the IFNgamma-STAT1-XBP1s-IRF1 axis and remodeling the TME via chemokines such as CCL20 that recruit immunosuppressive cell populations. The combination of an IRE1alpha inhibitor and anti-PD-1 antibody represents a promising strategy to enhance the efficacy of immunotherapy for NSCLC.