Virus-driven remodeling of the immune microenvironment and response to immune checkpoint inhibitors: the infection- immunity-cancer crosstalk

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of diverse solid tumors; however, concurrent viral infections significantly influence their efficacy and safety profiles. By driving persistent antigen exposure, inducing T cell exhaustion, and remodeling the immunosuppressive tumor microenvironment (TME), viruses extensively reconfigure tumor immune landscapes, leading to marked heterogeneity in responses to immunotherapy. Emerging evidence indicates that patients infected with hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human papillomavirus (HPV), or Epstein-Barr virus (EBV) who receive ICIs therapy may not only regain antitumor immune function, but in some cases may also be associated with virological responses, immunological changes suggestive of improved viral control. However, the risk of viral reactivation remains a concern, particularly in the context of immune-related adverse events (irAEs) requiring immunosuppressive treatment. This review systematically summarizes the current clinical application of ICIs across different viral infection backgrounds and highlights recent advances in the underlying immunological mechanisms. Furthermore, we propose the potential value of virus-specific immune profiling in guiding individualized treatment strategies and emphasize the need to optimize the integration of ICIs and antiviral therapies from the perspective of systemic immune reprogramming.

Keywords: Epstein–Barr virus (EBV); hepatitis B virus (HBV); hepatitis C virus (HCV); human immunodeficiency virus (HIV); human papillomavirus (HPV); immune checkpoint inhibitors; viral reactivation; virus-associated tumors.