TMED3, the transmembrane emp24 trafficking protein 3, is a membrane protein. It is involved in the ER stress-associated unconventional protein secretion (UPS) of transmembrane proteins like CFTR, pendrin and SARS-CoV-2 Spike. The heteromeric TMED2/3/9/10 complex mediates this UPS, with TMED3 recognizing the ER core-glycosylated protein cargos [1].

Knockdown of TMED3 has shown significant impacts in multiple cancer types. In endometrial carcinoma, it restrained cell cycle, growth and migration, while promoting apoptosis [2]. In ovarian cancer, TMED3 knockdown reduced cell viability and migration, increased apoptosis and inhibited tumor growth in xenograft models. It stabilizes SMAD2 by counteracting NEDD4-mediated ubiquitination to promote ovarian cancer [3]. Similar tumor-suppressing effects were seen in osteosarcoma, where TMED3 knockdown inhibited proliferation, migration and enhanced apoptosis in vitro and in vivo, and ribosomal protein S15A was identified as a downstream target [4]. In colorectal cancer, elevated TMED3 expression was associated with poor prognosis [5]. In esophageal squamous cell carcinoma, knocking down TMED3 inhibited cell proliferation, migration, invasion and promoted apoptosis in vitro and inhibited tumorigenicity in vivo [6]. In malignant melanoma, depletion of TMED3 arrested development in vitro and in vivo, and it promotes development by targeting CDCA8 and regulating the PI3K/Akt pathway [7]. In lung squamous cell carcinoma, TMED3 knockdown regulated cell function, inhibited tumor growth in vivo, and EZR was identified as a potential target [8]. In non-small cell lung cancer, TMED3 silencing reduced cell proliferation, invasion and increased sensitivity to cisplatin, and it enhances the Wnt/β-catenin pathway via regulation of AKT [9]. In hepatocellular carcinoma, TMED3 knockdown suppressed metastasis in vitro and in vivo, and it promotes metastasis through IL-11/STAT3 signaling [10].

In conclusion, TMED3 plays a crucial role in the ER stress-associated UPS of transmembrane proteins. In addition, through gene knockdown (functionally similar to gene knockout in revealing gene function) in various cancer models, TMED3 has been shown to be a key player in promoting the progression of multiple cancers, highlighting its potential as a therapeutic target for these malignancies.