XBP1 signaling from tumor metabolic stress to myeloid driven immunotherapy resistance (Review).

The tumor microenvironment (TME) is a complex ecosystem with harsh conditions, such as hypoxia, nutrient deprivation, metabolic acidosis and oxidative stress, that promote tumor progression and shape immune responses. In this environment, endoplasmic reticulum stress and the unfolded protein response are activated, with the transcription factor X‑box binding protein 1 (XBP1) serving a key role. XBP1 not only maintains cell protein homeostasis, but also modulates the generation, metabolic adaptation and immunosuppressive function of myeloid‑derived suppressor cells (MDSCs). The TME and tumor‑derived factors, such as exosomes, remotely activate XBP1 in MDSCs, enhancing their survival and immunosuppressive capability by reprogramming lipid and glucose metabolism and upregulating the expression of arginase‑1, inducible nitric oxide synthase, reactive oxygen species and immunosuppressive cytokines. The present review aimed to describe the TME stress‑XBP1‑MDSC‑immunosuppression axis, its molecular mechanisms and the role of XBP1 in MDSC heterogeneity and plasticity. Targeting XBP1 may enhance the efficacy of existing therapies, particularly immune checkpoint blockade, by alleviating MDSC‑mediated immunosuppression, offering a novel paradigm for understanding and reversing tumor immune escape.