Reprogramming the tumor immune microenvironment via antibody-drug conjugates

INTRODUCTION: Antibody-drug conjugates (ADCs) have revolutionized oncology, yet tumor microenvironment (TME) heterogeneity remains a major barrier. TME-targeted ADCs offer a paradigm shift by specifically modulating immunosuppressive cellular crosstalk and stromal components to overcome tumor evasion. AREAS COVERED: This review summarizes design strategies and clinical progress of TME-targeted ADCs. Literature was searched via PubMed and Embase (2015-2025), focusing on early-phase trials, safety profiles, and translational challenges in advanced solid tumors. EXPERT OPINION: The next decade will transition from broad TME disruption to precision engineering. AI-driven spatial omics will refine biomarker-led selection, identifying 'TME phenotypes' for tailored therapy. Emerging multi-immune-axis platforms, such as immunostimulatory antibody conjugates (ISACs) and bispecific ADCs, will transcend single-target limitations. We anticipate regulatory approvals of TME-targeted ADCs for 'cold' tumors within five years, serving as priming agents for immunotherapy. Within ten years, TME-targeted ADCs should migrate to neoadjuvant settings to 'normalize' the tumor ecosystem before surgery. This evolution from treatment in advanced settings to foundational curative therapy, using personalized ADC combinations tailored to individual immune landscapes, will be essential to overcome adaptive resistance and achieve long-term remission.