Challenges for CAR-T cell therapy in multiple myeloma: overcoming the tumor microenvironment

Chimeric antigen receptor T (CAR-T) cell therapy has shown promising efficacy in multiple myeloma (MM) patients, leading to FDA approval of two B cell maturation antigen (BCMA)-specific CAR-T cell therapies (ide-cel and cilta-cel). Despite the remarkable response rates and response depth of MM patients to CAR-T cell therapy, patients inevitably relapse. A growing body of evidence suggests that the activity of CAR-T cells is affected by the immunosuppressive tumor microenvironment (TME). In this review we have summarized the main challenges that CAR-T cells face in the TME, including various immunosuppressive cells, structural components, hypoxia, nutrient starvation, and metabolism. Moreover, we also discussed some candidate strategies for CAR-T cell therapy to overcome immunosuppressive TME and improve the efficacy of CAR-T cell therapy in the treatment of MM.