Targeting Toll-like Receptors to Enhance Oncolytic Virotherapy: Strategies and Emerging Perspectives

Oncolytic virotherapy (OVT) is a promising anticancer strategy, owing to its capacity to lyse tumor cells selectively and remodel the tumor microenvironment (TME) to enhance antitumor efficacy. Despite the continuous introduction and investigation of newly engineered oncolytic viruses (OVs) in clinical trials, their clinical translation remains limited, with Toll-like receptor (TLR)-mediated host immune responses representing a critical influencing factor. TLRs constitute a family of structurally conserved transmembrane proteins distributed on the plasma membrane and endosomal membranes. They initiate innate immune responses by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and are essential for dendritic cells (DCs) maturation, playing a pivotal regulatory role across diverse tumor therapies. However, TLRs may also restrict viral replication and spread, and some studies suggest that they could, under certain conditions, act as drivers of tumor progression. Nonetheless, the role of TLRs in OVT has not been comprehensively summarized to date. In this review, we synthesize recent advances in the application of TLRs in OVT, with particular attention to their mechanisms of action and the challenges that remain to be overcome, and consider their prospects in oncology, offering insights that may inform the clinical translation of this therapeutic approach.