The TNRC6B/circTNRC6B axis drives lymphovascular invasion and metastasis through an intragenic self-degradation loop

Lymphovascular invasion (LVI) is a critical early step in metastasis, yet the mechanisms remain elusive. We identify an intragenic antagonistic loop between TNRC6B and circTNRC6B that determines LVI and metastasis in esophageal squamous cell carcinoma. This antagonism is conserved across upper gastrointestinal tumors, where TNRC6B expression correlates positively with LVI and poor prognosis, while circTNRC6B shows the opposite associations. TNRC6B protein degrades circTNRC6B via its middle domain, which otherwise functions as a potent tumor suppressor. Mechanistically, circTNRC6B recruits HNRNPA2B1 in an m6A-dependent manner to orchestrate the nuclear-to-cytoplasmic translocation of KLRC3 mRNA. Concurrently, circTNRC6B acts as a molecular decoy, competing with IGF2BP2 for USP4 binding to impair IGF2BP2 deubiquitination, further destabilizing KLRC3 mRNA. Notably, HNRNPA2B1 mediates the exosomal packaging of m6A-modified circTNRC6B to counteract TNRC6B driven pro-tumorigenic effects. This study highlights the TNRC6B/circTNRC6B axis as a key determinant for LVI, providing potential diagnostic biomarkers and therapeutic targets for upper gastrointestinal tumors.