Researchers have uncovered a key mechanism by which cancer-associated fibroblasts (CAFs) drive oxaliplatin resistance and stemness in colorectal cancer (CRC) through the CAF–lactate–ANTXR1 axis. A glycolytically active CAF subset (resCAFs) produces excess lactate via high MCT4 and LDHA expression, which modifies cancer cell behavior.
Lactate induces histone lactylation (H3K18la), activating ANTXR1 transcription, and directly lactylates ANTXR1 at lysine 453. This triggers the RhoC/ROCK1/SMAD5 pathway, enhancing stemness, survival, and resistance. In vitro and xenograft studies showed that blocking lactate transport between CAFs and tumor cells restored oxaliplatin sensitivity. ResCAF-derived lactate also increased stemness markers such as LGR5, MYC, and SOX2, promoting tumor growth and self-renewal.
These findings identify lactate-driven ANTXR1 lactylation as a central driver of CAF-induced chemoresistance. Targeting the lactate shuttle or ANTXR1 signaling could provide a promising strategy to overcome drug resistance and improve therapeutic outcomes in CRC.