Targeting TMEM45A, a regulator of endoplasmic reticulum stress, inhibits tumor growth and enhances 5-FU sensitivity in gastric and cervical cancer

According to Global Cancer Statistics 2022, gastric cancer (GC) and cervical cancer (CC) rank among the top five tumors in terms of incidence and mortality for males and females, respectively. Despite significant advancements in diagnosis and treatment, chemoresistance remains a formidable challenge, leading to suboptimal patient outcomes. Notably, endoplasmic reticulum (ER) stress is a key cellular stress response: previous studies have shown that excessive protein folding burden activates the unfolded protein response and induces autophagy, an important driver of 5-fluorouracil (5-FU) resistance in cancer cells. Thus, elucidating ER stress-related resistance mechanisms and identifying therapeutic targets are critical. We identified TMEM45A, an ER stress-associated gene, which is highly expressed in GC and CC and correlates with poor prognosis. Under ER stress, elevated TMEM45A stimulates ROS production, promotes TFEB nuclear translocation, and up-regulates UVRAG, inducing cytoprotective autophagy that mitigates ER stress and indirectly enhances cancer cell proliferation. Notably, TMEM45A knockdown enhanced 5-FU efficacy in BALB/c nude mouse xenografts, with tumor weight showing a 4.06-fold higher suppression than 5-FU monotherapy ( P < 0.0001). Collectively, our study uncovers an ER stress–TMEM45A–autophagy loop mediating chemoresistance. TMEM45A may serve as a promising therapeutic target ( e.g. , small-molecule inhibitors, siRNA-loaded nanocarriers combined with 5-FU) and prognostic biomarker, with its expression monitoring aiding in identifying high-risk cancer patients for intensive adjuvant therapy or surveillance.