ABSTRACTPersistent and intense endoplasmic reticulum (ER) stress is widely acknowledged as a hallmark of tumorigenesis. To restore ER homeostasis, cells activate the unfolded protein response (UPR), which is aberrantly regulated in cancer cells. This review provides an in‐depth analysis of the mechanisms through which the UPR facilitates tumor progression. The UPR is activated by ER stress sensors such as inositol‐requiring enzyme 1 (IRE1α), protein kinase R‐like ER‐resident kinase (PERK), and activating transcription factor 6 (ATF6). These sensors regulate cancer cell proliferation, immune evasion, metastasis, and drug resistance. We summarize the crosstalk between the UPR and multiple signaling pathways, including mTOR, MAPK, and NF‐κB, which collectively promote tumor growth and metastasis. Additionally, we discuss the role of the UPR in modulating the tumor microenvironment to support angiogenesis and immune evasion. We also provide an overview of pharmacological agents targeting specific UPR pathways, such as GRP78 inhibitors, IRE1α inhibitors, PERK inhibitors, and ATF6 inhibitors, with the aim of developing more effective cancer therapies. This comprehensive review highlights the potential of targeting the UPR as a novel strategy for cancer treatment and underscores the need for further research to elucidate the complex interactions between the UPR and cancer progression.