Targeting XBP1 in Cancer: A Review of Therapeutic Approaches and Strategies

Abstract: X-box binding protein 1 (XBP1) is an essential unfolded protein response (UPR) transcription factor that has important roles in cancer biology. Malignant XBP1 signaling promotes tumor survival, drug resistance, and immune evasion and thus represents a potential therapeutic target and biomarker. A structured literature search was conducted using PubMed, Embase, Springer, Elsevier, ISI Web of Knowledge, and Google Scholar. The studies that had investigated the expression, role, and therapeutic targeting of XBP1 in various cancers were identified and critically assessed. XBP1 overexpression is associated with aggressive phenotypes, metastasis, and drug resistance to chemotherapy, radiotherapy, and endocrine therapy in many cancers, including breast, colorectal, lung, ovarian, liver, prostate, and hematopoietic cancers. Aside from intrinsic tumor activities, XBP1 also modulates the tumor microenvironment by suppressing dendritic cell function, promoting T-cell exhaustion, and reprogramming. Preclinical data support that inhibiting the IRE1α–XBP1 pathway restores treatment sensitivity and shows synergy with immunotherapy. XBP1 is a molecular interface for ER stress adaptation, oncogenic progression, and immune modulation. The fact that XBP1 is both a prognostic biomarker and a therapeutic target underscores the translational potential of XBP1-targeted therapy to improve the outcome of cancer.