Breast cancer has surpassed lung cancer to become the most commonly diagnosed cancer in women worldwide. Sigma-2 (σ2) receptor is considered to be a potential therapeutic target for breast cancer because of its high expression in breast cancer cells and low expression in normal breast cells. Many σ2 ligands have been reported to have excellent anticancer activity, but their mechanism of action has not been fully elucidated. We discovered that A011 had high affinity and selectivity for σ2 receptor, reduced proliferation in five cancer cell lines, and significantly inhibited the monoclonal formation ability of MCF-7 cells. Furthermore, A011 rapidly increased the levels of intracellular Ca2+ and reactive oxygen species and induced autophagy. Molecular pharmacology studies revealed that A011 induced endoplasmic reticulum stress, activated the PERK-eIF2α-CHOP pathway and inhibited the activation of the PI3K-Akt-mTOR pathway, leading to cell apoptosis. In an in vivo tumor model, A011 showed obvious anti-tumor activity and no significant toxicity. More importantly, our study demonstrated for the first time that endoplasmic reticulum stress is the main mechanism of anti-cancer effects for σ2 ligands, at least for A011. A011 may potentially be useful as a therapeutic agent for treating breast cancer.Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.