Recent advances in Tumor microenvironment-responsive pro-antibody to overcome on-target, off-Tumor toxicity.

In recent years, monoclonal antibodies(mAbs) have become a new type of drug for disease treatment. Especially, the bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies, all derived from targeting properties of mAbs, have achieved great success in the field of tumor treatment. However, due to the low expression of tumor-associated antigens in normal tissues, the "on-target, off-tumor" toxicity produced by these therapies has limited their development. To solve this problem, researchers have designed protease-activated, low pH-sensing, and high extracellular ATP-responsive pro-antibodies leveraging the special biochemical conditions of the tumor microenvironment (TME). This review summarizes the mechanism of action, recent advances, and the limitations of different TME-responsive pro-antibodies. Given the relative maturity of the protease-activated platform, its applications have been extended to bispecific antibodies, ADCs, and CAR-T cell therapies, which are also summarized in this review. Finally, we discuss the problems faced in the clinical translation of TME-responsive pro-antibodies low production yield and the lack of suitable preclinical animal models for safety assessment. In summary, this review provides a new perspective on the development of safe and efficient next-generation antibody therapies.