Antibody-drug conjugates in colorectal cancer: molecular design, preclinical advances, and translational challenges

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, largely because of tumor heterogeneity, therapeutic resistance, and the limited efficacy of existing targeted therapies in advanced disease. Antibody-drug conjugates (ADCs) have emerged as a promising class of targeted anticancer therapeutics that combine the specificity of monoclonal antibodies with the cytotoxic potency of highly active payloads, thereby enabling selective tumor cell killing while minimizing systemic toxicity. Although ADCs have demonstrated substantial clinical success in several solid and hematological malignancies, their translation to CRC has been relatively limited, underscoring the need for a focused evaluation of CRC-specific ADC development. This review provides a comprehensive and critical overview of recent advances in ADC design and preclinical development for CRC, with emphasis on molecular architecture, linker-payload chemistry, antigen selection, and pharmacological mechanisms of action. Key components of ADCs, including antibody formats, cleavable and noncleavable linkers, and cytotoxic payload classes such as auristatins, maytansinoids, duocarmycins, and topoisomerase inhibitors, are discussed in the context of optimizing the therapeutic index and tumor selectivity. Mechanistic aspects of ADC activity, including antigen-mediated internalization, intracellular trafficking, payload release, and the bystander effect, are highlighted for their relevance to heterogeneous CRC tumors. This review systematically summarizes emerging preclinical ADC candidates targeting CRC-associated antigens, including EGFR, CEACAM5, c-Met, RON, DDR1, GPR56, LGR5, Claudin-2, and CD98hc. Finally, key translational challenges-including antigen heterogeneity, limited internalization, and off-target toxicity-are discussed alongside future perspectives emphasizing biomarker-driven patient selection and rational ADC design.