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. 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.

While novel therapies such as rituximab and polatuzumab vedotin have led to improved outcomes, approximately 35% of patients eventually develop relapsed or refractory disease. Among these, miR-155 and miR-21 are particularly well studied, playing central roles in both tumor progression and remodeling of the tumor microenvironment. This review summarizes current evidence on the biological and clinical relevance of miRNAs in DLBCL, emphasizing their diagnostic and prognostic potential.

P1, N=30, Suspended, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Jun 2027 | Recruiting --> Suspended | Trial primary completion date: Jun 2026 --> Jun 2027

P3, N=1130, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P2, N=39, Active, not recruiting, University of Rochester | Recruiting --> Active, not recruiting

P2, N=34, Active, not recruiting, Washington University School of Medicine | Trial completion date: May 2031 --> Apr 2029 | Trial primary completion date: May 2026 --> Sep 2025

P2, N=152, Recruiting, Ruijin Hospital | Not yet recruiting --> Recruiting

P4, N=600, Recruiting, Henan Cancer Hospital; Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital

P1, N=165, Recruiting, AbbVie | Trial primary completion date: Nov 2031 --> Jan 2027

P1/2, N=12, Recruiting, Washington University School of Medicine | Trial completion date: May 2031 --> May 2032 | Trial primary completion date: May 2026 --> May 2027

These findings suggest that polatuzumab vedotin-induced CD20 upregulation provides a molecular rationale to explain the synergistic effect of this combination therapy. The authors have confirmed clinical trial registration is not needed for this submission.

R-CHOP remains the frontline standard, with polatuzumab-R-CHP conferring a subgroup-dependent progression-free survival gain, yet early relapse and primary refractoriness persist. On the other side, CNS risk assessment is best approached with CNS-IPI refined by site and genotype; prophylaxis remains individualized given mixed efficacy signals. Overall, risk-adapted, biologically driven care should report NCCN-IPI (alongside IPI) in all patients and incorporate imaging burden, genomics, and ctDNA where feasible.