Preventing postsurgical colorectal cancer relapse: A hemostatic hydrogel loaded with METTL3 inhibitor for CAR-NK cell therapy

Abstract

Colorectal cancer (CRC) recurrence post-surgery remains a major challenge. While Chimeric Antigen Receptor (CAR)-engineered natural killer (NK) cells hold immense therapeutic potential, their intratumoral infiltration ability remains limited, hampering efficacy. Building upon prior research suggesting that chemokines like C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10) recruit CAR-NK cells, we hypothesized that tumor cell m6A methylation, regulated by Methyltransferase-like 3 (METTL3), influences chemokine secretion. This study aims to elucidate the underlying mechanisms and improve METTL3 inhibition efficiency. We designed an adhesive hemostasis hydrogel loaded with STM2457, a METTL3 inhibitor, aimed at sustained release in the acidic tumor microenvironment. In vitro, the hydrogel promoted CAR-NK cell recruitment and tumor killing via sustained METTL3 inhibition. The hydrogel's Schiff base bonds further enabled intestinal adhesion and hemostasis in an incomplete tumor resection model of CRC. Combining the hydrogel with CAR-NK cell therapy significantly reduced CRC recurrence in vivo. Overall, our study reveals the crucial role of METTL3 in CRC recurrence and proposes a promising, multimodal strategy using STM2457-loaded hydrogel and CAR-NK cells for enhanced therapeutic efficacy.

Keywords

• Colorectal cancer
• CAR-NK cells adoptive therapy
• Injectable hydrogel
• N6-methyladenosine modification
• METTL3