Reprogramming the tumor microenvironment: synergistic mechanisms of antibody–drug conjugates and immune checkpoint inhibitors

Abstract The integration of antibody–drug conjugates (ADCs) with immune checkpoint inhibitors (ICIs) represents a paradigm shift in oncology, combining targeted cytotoxicity and adaptive immune activation to overcome resistance in refractory tumors. This review explores their mechanistic synergy, focusing on dual functions in reprogramming the tumor immune microenvironment. ADCs mediate antibody-dependent cellular cytotoxicity (ADCC), engaging NK cells and macrophages to release tumor-associated antigens (TAAs) and damage-associated molecular patterns. Immunogenic cell death (ICD) amplifies adaptive immunity by releasing TAAs for T-cell priming, while PD-L1 upregulation creates a targetable niche for PD-1/PD-L1 inhibitors. This strategy sustains interferon-γ signaling and drives effector T-cell differentiation, but overlapping immunostimulatory signals raise risks of cytokine release syndrome and immune-related adverse events, requiring biomarker-guided risk stratification. We propose a multidimensional immune microenvironment reprogramming framework, integrating tumor-infiltrating lymphocyte phenotyping, serum biomarkers, and spatial transcriptomic mapping, to optimize ADC–ICI therapy and balance efficacy with immunopathology.