Expanding the horizons of cancer therapy with next-generation 4-1BB agonists: a review of molecular and clinical strategies to maximize efficacy and ensure safety.

Driven by the substantial limitations of first generation 4-1BB agonists urelumab and utomilumab, the field has shifted toward engineering next-generation molecules with improved therapeutic windows. This review provides a comprehensive analysis of this evolution, detailing how key molecular design strategies are used to restrict 4-1BB activation to the tumor microenvironment. We summarize available clinical data, highlighting that 4-1BB bispecific antibodies exhibit superior antitumor efficacy and more favorable safety profiles compared with their monospecific predecessors. Furthermore, we discuss strong rationale for combination strategies, emphasizing how 4-1BB signaling provides the crucial costimulatory signal necessary to sustain durable anti-tumor responses. In summary, this review elucidates the scientific basis of antibody engineering aimed at improving safety and tumor-selective activation of 4-1BB agonists and outlines future directions for optimizing their clinical application in cancer immunotherapy.