HIV-driven tumor ecosystem: from chronic immune dysfunction to cancer evolution

Although HIV-associated malignancies have been reviewed separately through the lens of individual oncogenic viruses (KSHV, EBV, HPV) or immune dysfunction in isolation, no prior synthesis has integrated these processes into a single, systemic “tumor ecosystem” framework spanning virology, immunology, the tumor microenvironment, and clinical treatment response. Human immunodeficiency virus (HIV) infection profoundly alters the immune landscape, establishing a distinctive tumor ecosystem characterized by chronic immune dysfunction, inflammatory microenvironment remodeling, and virus-driven oncogenic mechanisms that collectively promote cancer initiation and progression. Despite advances in antiretroviral therapy (ART), HIV-infected individuals remain at increased risk for various malignancies, underscoring the complex interplay between persistent immune impairment and tumor evolution. This review comprehensively examines the components and dynamic changes within the tumor ecosystem of HIV-infected patients, focusing on how HIV-mediated CD4+ T-cell depletion, immune checkpoint dysregulation, chronic antigenic stimulation, and direct effects of viral proteins such as Tat and Nef facilitate tumor immune evasion and genomic instability. Integrating insights from cutting-edge single-cell omics, spatial transcriptomics, and animal model studies, we delineate the evolutionary trajectories of diverse HIV-associated cancers, including lymphomas and Kaposi's sarcoma. Furthermore, we critically evaluate the impact of ART on modulating the tumor microenvironment and immune responses, alongside emerging immunotherapeutic approaches such as immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies. By systematically synthesizing molecular mechanisms, clinical manifestations, and therapeutic advancements, this review aims to provide a comprehensive theoretical framework to guide precision prevention and treatment strategies for HIV-related malignancies. By integrating virological, immunological, and single-cell/spatial evidence into an ecosystem-level model, this review addresses this gap and offers direct implications for immunotherapy stratification and precision management of HIV-associated malignancies.