Harnessing multispecific antibodies for next-generation cancer treatments

Multispecific antibodies (MsAbs), capable of targeting multiple antigens simultaneously, are regarded as the 2.0 version of monoclonal antibodies (mAbs), providing therapeutic benefits that significantly exceed those of mAbs. This enhanced functionality makes MsAbs a particularly promising strategy for treating solid tumors. In this comprehensive review, we summarize diverse targeting strategies, clinical trial outcomes, and existing hurdles, while proposing novel directions to enhance the development of MsAbs for overcoming the immunosuppressive tumor microenvironment (TME). Based on their therapeutic mechanisms, we categorize their actions into six principles: 1) blocking various oncogenic signaling pathways; 2) activating and redirecting cytotoxic immune cells toward tumor cells; 3) enhancing macrophage-mediated phagocytosis; 4) targeting immune checkpoints to alleviate immunosuppression; 5) modulating matrix components within the immunosuppressive TME; and 6) promoting immune cell infiltration and localized cytokine signaling. In addition, the integration of MsAbs with sophisticated technologies has opened new avenues for enhancing therapeutic efficacy. These approaches include antibody-degrader conjugates, chimeric antigen receptor T cell (CAR-T) therapies, antibody-oncolytic virus combinations, nanomaterial-based delivery systems, and messenger RNA (mRNA)-based technologies. Such innovative strategies highlight the transformative potential of MsAbs, positioning them at the forefront of next-generation cancer immunotherapies.