From Divergent Pathogenesis to Precision Medicine: The Road to Targeted Therapy in HIV-Associated and HIV-Unrelated Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common and biologically heterogeneous subtype of non-Hodgkin lymphoma. While immunochemotherapy has improved outcomes, survival remains variable due to substantial molecular diversity. In people living with HIV (PLWH), DLBCL is the predominant lymphoma subtype and demonstrates more aggressive clinical behaviour, characterised by advanced-stage disease, extranodal involvement, and a potentially poorer prognosis despite antiretroviral therapy. Clarifying differences in the pathogenesis of HIV-associated and HIV-unrelated DLBCL is essential for informing precision therapies. This narrative review highlights the contrasting pathogenic mechanisms, with an emphasis on the interplay between viral oncogenesis, host immunity, and molecular alterations in HIV-associated DLBCL versus DLBCL in immunocompetent individuals. Understanding these differences is critical for refining diagnostic approaches, improving risk stratification, and identifying novel therapeutic strategies tailored to both groups.