Nattokinase-driven remodeling of tumor microenvironment enhances the efficacy of MSLN-targeted CAR-T cell therapy in solid tumors.

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies but faces significant challenges in solid tumor therapy. The tumor microenvironment (TME) of solid tumors, including the dense extracellular matrix (ECM) and immunosuppressive factors, creates physical and biochemical barriers that hinder CAR-T cell infiltration, function, and persistence. Despite advances in CAR-T cell engineering, overcoming these TME barriers remains a major obstacle. The ECM in solid tumors restricts CAR-T cell penetration and limits their antitumor efficacy. Recent studies have explored ECM modulation as a strategy to enhance CAR-T therapy. Nattokinase (NKase), a natural fibrinolytic enzyme, has shown potential in degrading ECM components, promoting TME remodeling, and improving therapeutic responses. In this study, we evaluate the therapeutic efficacy of NKase in combination with MSLN-targeted CAR-T cells for solid tumors. We hypothesize that NKase will reduce tumor fibrosis by degrading ECM components, facilitating CAR-T cell infiltration and enhancing their cytotoxic activity. In vitro and in vivo experiments will assess the effects of NKase on CAR-T cell infiltration, activation, memory phenotype maintenance, and antitumor activity. This study aims to optimize CAR-T therapy for solid tumors and supports the clinical potential of NKase as an adjunctive therapeutic agent.