Abstract
BACKGROUD: Oesophageal cancer ranks among the most prevalent malignant tumours globally, primarily consisting of oesophageal squamous cell carcinoma (ESCC). Cancer stem cells (CSCs) accelerate the progression ESCC via their strong self-renewal and tumourigenic capabilities, presenting significant clinical challenges due to increased risks of recurrence and drug resistance. METHODS: Our previous study has reported WYC-209, which is capable of inducing apoptosis of CSCs in melanoma and hepatoma, but is ineffective against ESCC. Additionally, clinical studies in ESCC still lack drug candidates that effectively target CSCs. Therefore, our team developed a series of novel retinoids that target retinoic acid receptors (RARs), with enhanced potency, broader efficacy and minimised toxic side effects against CSCs. Following iterative optimisation and pharmacological validation, ZSH-2208 was identified as the most promising candidate for effectively targeting ESCC tumour-repopulating cells (TRCs). Mechanistic exploration revealed that ZSH-2208 inhibits the growth of ESCC-TRCs through modulation of the RARγ-TNFAIP3 axis. The clinical significance of the key molecule TNFAIP3 in ESCC has also been demonstrated. RESULTS: This study introduces ZSH-2208, a novel retinoid specifically targeting ESCC-TRCs, which holds significant potential for clinical application in ESCC. KEY POINTS: The ESCC-TRCs replicates the characteristics of ESCC stem cells, which are inhibited by ZSH-2208. In vivo and in vitro experiments demonstrated that ZSH-2208, a novel RA analogue, effectively inhibits the growth of ESCC-TRCs through the RARγ-TNFAIP3 axis. Low levels of TNFIP3 protein may be associated with improved survival probability in ESCC patients.