Oncolytic Viruses Reshape PD-1/PD-L1 Signaling: Mechanisms and Clinical Synergy With Immune Checkpoint Blockade

Abstract

Oncolytic viruses (OVs) are naturally occurring or genetically engineered viruses that selectively target and destroy cancer cells. They act through multiple mechanisms, including direct tumor cell lysis, stimulation of immune-mediated cytotoxicity, and modulation of the tumor microenvironment (TME). Recent studies have shown that, beyond their direct oncolytic activity, OVs also influence the immune landscape by modulating the expression of PD-1/PD-L1 axis. In many cases, OVs trigger the release of proinflammatory cytokines, leading to increased PD-L1 levels on immune cells. This upregulation plays a key role in modulating the TME and shaping immune checkpoint signaling. While there is also evidence that OVs can directly reduce PD-L1 expression on tumor cells, the most prominent effect appears to be the boost in PD-L1 expression. This shift is thought to be crucial in influencing how the immune system responds to tumors. These changes could modulate PD-L1-mediated immune suppression and alter the exhaustion and anergy rate of the effector tumor-specific T cells infiltrated into the TME. This review discusses how OVs influence PD-1 and PD-L1 expression, with a focus on innate and adaptive immune activation, interferon signaling pathways, and engineered OVs designed to express immunomodulatory cytokines and chemokines. We explore how these mechanisms can be leveraged to enhance antitumor immunity, particularly in combination with ICIs. Furthermore, we discuss the potential of OVs to remodel the TME, modulate PD-L1 expression, and promote immune-mediated tumor clearance. Overall, this review highlights the evolving role of OVs in cancer therapy and their potential to augment the effectiveness of current immunotherapeutic strategies.