The development of solid tumors like melanomas is driven by cancer stem cells (CSCs). These cells can also promote tumor growth, dormancy, metastasis, recurrence, and chemoresistance, which contribute to poor cancer outcomes. An intracellular degradation/recycling pathway called autophagy is thought to regulate the “stemness” of CSCs to enable these effects. To clarify the mechanism, a recent study examined CSCs isolated from human melanoma cell lines. The expression of the molecule Sec23a was lower in the CSCs than in the original melanoma cells, and the reduced Sec23a expression was associated with increased stemness in vitro and tumor growth in vivo, indicating a negative correlation between Sec23a and CSC stemness. Further experiments revealed that Sec23a downregulation increases CSC stemness by promoting autophagy. Specifically, Sec23a downregulation enhances endoplasmic reticulum (ER) stress, which leads to upregulation of the ER stress-responsive protein FAM134B. The upregulation of FAM134B in turn increases ER-specific autophagy (ER-phagy), thereby promoting self-renewal and stemness. Although more research is needed, this study helps elucidate the mechanism of CSC stemness regulation and suggests that Sec23a is a favorable diagnostic and prognostic biomarker in melanoma. Furthermore, it indicates that Sec23a and FAM134B might be useful targets for melanoma treatment.