Viral oncogenesis and immune remodeling: Decoding the therapeutic potential of immune checkpoint inhibitors in virus-associated cancers

Various viruses are widely recognized as key contributors to the development of numerous hematological malignancies and solid tumors. It is estimated that virus-associated cancers account for approximately 1.5 million new cases globally each year. The major oncogenic viruses include Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), hepatitis B and C viruses (HBV and HCV), human papillomavirus (HPV), human T-cell lymphotropic virus type 1 (HTLV-1), and Merkel cell polyomavirus (MCPyV). Notably, human immunodeficiency virus (HIV), though non-oncogenic itself, exacerbates malignancy risk through profound immunosuppression. Virus-associated tumors frequently exhibit intricate immune evasion mechanisms, influencing both disease progression and therapeutic outcomes. Immune checkpoint inhibitors (ICIs) have demonstrated clinical promise in this context. However, monotherapy remains constrained by suboptimal efficacy and acquired resistance. Emerging evidence highlights the synergistic potential of combining ICIs with both virus-directed immunotherapies, including therapeutic vaccines, TCR-T/CAR-T cells, and oncolytic viruses, and other targeted or anti-angiogenic agents to reverse T cell exhaustion, enhance tumor control, and achieve dual antiviral/antitumor efficacy. This review summarizes oncoviral molecular mechanisms, integrates representative clinical trial evidence on the use of ICIs in virus-driven malignancies, and evaluates emerging combinatorial strategies. Future directions should emphasize biomarker-driven approaches and rational immunotherapy design to address the complex challenges in this evolving field.