Antibody–drug conjugates in colorectal cancer: target biology, resistance, and the clinical-trial landscape

Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality, and outcomes in microsatellite-stable metastatic disease have improved only modestly despite optimised cytotoxic, anti-VEGF and anti-EGFR regimens. Antibody–drug conjugates (ADCs) link tumour-associated antigen targeting to intracellular delivery of potent payloads, but their place in CRC is still being defined. We outline core design principles (target/antibody, linker, payload) and summarise clinical experience with constructs of direct or indirect relevance to CRC (trastuzumab deruxtecan, sacituzumab govitecan, trastuzumab emtansine). We then map the global CRC ADC pipeline using Trialtrove Clinical Intelligence and major registries, identifying 214 phase I–III studies. Disease-specific development streams are reviewed, focusing on HER2-, CEACAM5-and TROP2-directed ADCs, combination approaches pairing HER2-directed ADCs with chemotherapy or anti-angiogenic therapy, and next-generation concepts including LGR5-axis targeting and EGFR-based conjugates for stem-like or chemoresistant disease. Finally, we discuss class-wide challenges—treatment-related toxicities, primary and acquired resistance, and the need for harmonised biomarker strategies—and highlight how nanotechnology-enabled delivery and AI-guided target/biomarker optimisation may support more precise deployment. Overall, ADCs are a rational but early-stage option for biomarker-selected CRC, with clear activity in subsets and open questions on dosing, sequencing, combinations and long-term safety.