Preventing postsurgical colorectal cancer relapse: A hemostatic hydrogel loaded with METTL3 inhibitor for CAR-NK cell therapy
Zilin Tan, Liangjie Tian, Yang Luo, Kexin Ai, Xuehua Zhang, Haitao Yuan, Jinfan Zhou, Guangyao Ye, Shuofei Yang, Ming Zhong, Gaohua Li, Yanan Wang
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. This schematic illustrates the process of preparing GOSM-gel and the combination therapy strategy involving tumor excision, GOSM-gel administration, and CAR-NK cells injection for CRC. GOSM-gel, injected at the tumor resection site margin, forms an adhesive gel at the targeted location. The in-situ production of the hydrogel is triggered by the upregulation of CXCL9 and CXCL10 through the downregulation of METTL3, enhancing the therapeutic efficacy of CAR-NK cells infusion. • An in situ injection hydrogel for colorectal cancer after resection was developed. • The gel has excellent adhesive and hemostatic properties for clinical application. • The gel can regulate m6A methylation and accumulate CAR-NK cells to kill cancer.