TMED3, short for transmembrane emp24 trafficking protein 3, is a membrane protein involved in intracellular protein transport. It plays a critical role in the ER stress-associated unconventional protein secretion (UPS) of transmembrane proteins like CFTR, pendrin, and SARS-CoV-2 Spike [1]. In this process, the heteromeric TMED2/3/9/10 complex mediates the UPS of these cargos.

Knockdown of TMED3 has shown inhibitory effects on the progression of multiple cancers. In osteosarcoma, its knockdown suppressed proliferation, impeded migration, and enhanced apoptosis in vitro and inhibited tumor generation in vivo. The ribosomal protein S15A was identified as a potential downstream target involved in this process [2]. Similar results were seen in endometrial carcinoma, where TMED3 knockdown restrained cell cycle, growth, and migration, and promoted apoptosis both in vitro and in vivo, potentially through targeting PI3K/AKT signaling pathways [3]. In ovarian cancer, TMED3 knockdown led to reduced cell viability and migration, increased apoptosis, and inhibited tumor growth in xenograft models. It stabilized SMAD2 by counteracting NEDD4-mediated ubiquitination, promoting ovarian cancer progression [4]. In colorectal cancer, elevated TMED3 expression was associated with poor prognosis [5]. In lung squamous cell carcinoma, TMED3 knockdown inhibited cell proliferation, colony formation, apoptosis, and migration, and regulated EMT, with EZR being a potential downstream target [6]. In esophageal squamous cell carcinoma, TMED3 knockdown inhibited cell proliferation, migration, invasion, and tumorigenicity, and FAM60A was identified as a related protein [7]. In malignant melanoma, TMED3 depletion arrested tumor development in vitro and in vivo, and it regulated the PI3K/Akt pathway via CDCA8 [8]. In breast cancer, TMED3 promoted cell proliferation and migration by activating the Wnt/β-catenin signaling pathway [9]. In non-small cell lung cancer, TMED3 silencing reduced cell proliferation, invasion, and increased sensitivity to cisplatin, and it enhanced the Wnt/β-catenin pathway via regulation of AKT [10].

In conclusion, TMED3 is crucial for the ER stress-associated secretion of certain transmembrane proteins. Moreover, through gene knockdown studies in various cancer models, it has been demonstrated that TMED3 promotes the development and progression of multiple cancers, suggesting it could be a potential target for cancer therapies.