Beyond R-CHOP: The rise of antibody-drug conjugates in DLBCL

Diffuse large B-cell lymphoma (DLBCL) remains a therapeutic challenge, as a substantial proportion of patients experience relapsed or refractory (R/R) disease. Antibody-drug conjugates (ADCs) have emerged as a transformative class of targeted therapy, designed to deliver potent cytotoxic payloads directly to malignant cells via specific surface antigens. This approach enhances antitumor efficacy while minimizing toxicity. Recently, ADCs have expanded the DLBCL therapeutic landscape, with the approvals of CD79b-targeted polatuzumab vedotin and CD19-directed loncastuximab tesirine for R/R and even frontline disease. Additionally, numerous other ADCs targeting antigens such as CD22, CD30, and CD37 are under clinical investigation. However, the clinical application of ADCs is accompanied by challenges, including the management of characteristic toxicities, understanding and overcoming mechanisms of resistance. This review systematically synthesizes the mechanisms of action, updated clinical evidence, toxicity profiles, and resistance mechanisms of ADCs in DLBCL, while also discusses management strategies and provides perspectives on future directions.