Antibody-Drug Conjugates in Solid Tumor Oncology and the Frontier of Precision Immunosuppression: A Mechanistic, Translational, and Clinical Review

Antibody-drug conjugates (ADCs) have transitioned from clinically marginal agents into a defining therapeutic class for solid tumor oncology. In DESTINY-Breast03, trastuzumab deruxtecan achieved a four-fold progression-free survival advantage over trastuzumab emtansine, attributable not to antibody engineering but to the linker-payload axis: a cleavable peptide linker and a topoisomerase I payload with bystander activity. Sacituzumab govitecan extends the same logic to Trop-2-positive disease via extracellular payload release, and the framework now spans breast, urothelial, gynecologic, lung, gastric, and colorectal cancers, with enfortumab vedotin plus pembrolizumab displacing platinum chemotherapy as first-line therapy for urothelial cancer in EV-302 (median overall survival 31.5 versus 16.1 months). This review synthesizes ADC biology along three analytical axes. The mechanistic axis links each linker-payload-DAR configuration to a specific tumor-biology barrier: vascular limitation, which delivers approximately 0.1% of the administered dose to tumor tissue; the binding-site barrier, which concentrates exposure at the perivascular margin; and antigen mosaicism, which defeats internalization-dependent killing. The translational axis examines resistance as a coordinated failure across antigen modulation, trafficking, efflux, apoptotic execution, and lysosomal processing. The clinical axis traces the platform’s migration toward earlier-line and curative-intent settings. We close by examining whether the ADC delivery architecture translates to precision immunosuppression in autoimmune disease, where the glucocorticoid receptor modulator ADC ABBV-154 met placebo-controlled efficacy endpoints in rheumatoid arthritis but was discontinued because its benefit-risk profile did not differentiate it from existing biologic therapies.