Muscle atrophy is a major character of cancer cachexia, whose mechanism remains enigmatic. During cancer cachexia, the function of endoplasmic reticulum stress (ERS), which ubiquitously exists in invasive cancer, remains unclear in muscle remodeling. In addition, ERS can be transmitted to surrounding and distant cells, terming transmissible ERS (TERS), by certain soluble factors, which have not been completely identified. In this study, tunicamycin-induced conditioned media from oral squamous cell carcinoma (OSCC) cell lines were proved to transmit ERS to muscle cells both in vivo and in vitro. We found for the first time that exosomes from the conditioned media were the key factors to mediate TERS signaling and induce muscle cell atrophy and apoptosis consequently. Next-generation RNA sequencing was applied to pinpoint exosome miR-181a-3p, which was then identified to play a critical role in regulating ERS, muscle atrophy and apoptosis pathways. (C) 2020 Elsevier Inc. All rights reserved.