The ER stress-autophagy axis in cancer-induced muscle wasting: Unveiling the IRE1α/XBP1 pathway as a therapeutic target.

Abstract

Cancer cachexia is a multifactorial syndrome of progressive skeletal muscle wasting and functional decline that affects 50-80% of patients with advanced malignancies, frequently overlaps with sarcopenia, and contributes to 22-30% of cancer-related deaths. Effective therapies remain lacking, in part because the driving mechanisms are incompletely understood. Systemic inflammation-particularly interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)-has long been considered central to muscle wasting, yet cytokine-targeted trials have shown limited efficacy, prompting investigation of additional pathways. Among these, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have emerged as candidates, and this review focuses specifically on the IRE1α/XBP1 branch. The rationale rests on three observations from recent preclinical studies: XBP1s activity is increased in cachectic muscle; XBP1s occupies regulatory regions of autophagy-lysosome and ubiquitin-proteasome genes, a direct transcriptional link to protein degradation that distinguishes it from the translation-attenuating PERK and folding-oriented ATF6 branches; and genetic or pharmacological suppression of IRE1α/XBP1 attenuates wasting in these models. We examine how tumor-derived signals activate IRE1α/XBP1 to upregulate both the autophagy-lysosome pathway (ALP) and ubiquitin-proteasome system (UPS); its crosstalk with inflammatory (JAK-STAT3, NF-κB) and metabolic (mitochondrial dysfunction, fatty acid metabolism) networks; the evidence across cancer models and clinical contexts; and the therapeutic potential of IRE1α inhibitors, XBP1-directed strategies, and nutritional approaches including arginine. We frame the ER stress-autophagy axis as a mechanistically plausible, potentially tractable therapeutic target that requires further cross-model and clinical validation.