Abstract
Immune-stimulating antibody conjugates (ISACs) have emerged as a promising class of therapeutics, employing design principles similar to antibody-drug conjugates (ADCs) but replacing cytotoxic payloads with immune-stimulatory agents. These agents enhance immune system activation, enabling more effective tumor targeting and elimination. However, recent clinical setbacks since 2021 have raised concerns about ISACs' viability as ADC successors. Although ISAC development remains early-stage, clinical trials have revealed significant challenges, including limited efficacy, systemic toxicity (eg, cytokine release syndrome), and anti-drug antibody generation. Current strategies to overcome these hurdles focus on optimizing payload selection (eg, toll-like receptor 7(TLR7) vs stimulator of interferon genes (STING) agonists), improving linker stability, and exploring localized delivery methods. While ISACs face substantial translational barriers, their potential to synergize with existing immunotherapies and treat "cold" tumors maintains therapeutic promise. Further refinement of design parameters may ultimately position ISACs as a transformative oncology modality.