Abstract 2916: Tumor-intrinsic IRE1α signaling drives immune evasion and resistance to immune checkpoint inhibitor in lung cancer by upregulating PD-L1 and remodeling the tumor microenvironment

Abstract 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 IRE1α signaling, remains poorly understood. Here, we demonstrate that high IRE1α activity correlates with poor prognosis and resistance to immune checkpoint inhibitors in NSCLC patients. IRE1α 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 IRE1α (ERN1 KO) in immunocompetent mice significantly attenuated tumor growth and enhanced CD8+ T-cell infiltration. Mechanistically, IRE1α 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 IRE1α inhibitor MKC8866. Concurrently, IRE1α-XBP1s signaling synergized with IFNγ 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 IRE1α orchestrates immune evasion in NSCLC by amplifying tumor-intrinsic PD-L1 expression through the IFNγ-STAT1-XBP1s-IRF1 axis and remodeling the TME via chemokines such as CCL20 that recruit immunosuppressive cell populations. The combination of an IRE1α inhibitor and anti-PD-1 antibody represents a promising strategy to enhance the efficacy of immunotherapy for NSCLC. Citation Format: Youngjoo Jeon, Hyun Kyung Ahn, Hongsoon Kim, Sung-Yup Cho, Jaemoon Koh, Yoon Kyung Jeon. Tumor-intrinsic IRE1α signaling drives immune evasion and resistance to immune checkpoint inhibitor in lung cancer by upregulating PD-L1 and remodeling the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2916.