Lymphotropic Virotherapy Induces DC and High Endothelial Venule Inflammation, Promoting the Antitumor Efficacy of Intratumor Virus Administration.

Tumor-draining lymph nodes are a pivotal site for antitumor T-cell priming. However, their mechanistic roles in cancer immune surveillance and immunotherapy response remain poorly defined. Intratumor (IT) virotherapy generates antitumor T-cell immunity through multifaceted engagement of innate antiviral inflammation. In this study, we identify type-I interferon (IFNI) signaling in glioma-draining cervical lymph nodes as a mediator of IT polio virotherapy. Transient IFNI signaling after IT administration was rescued by cervical perilymphatic infusion (CPLI) virotherapy, targeting cervical lymph nodes directly. Dual-site (IT plus CPLI) virotherapy induced profound inflammatory reprogramming of cervical lymph nodes, enhanced viral RNA replication and IFNI signaling in dendritic cells and high endothelial venules, augmented antiglioma efficacy in mice, and was associated with T-cell activation in patients with recurrent glioblastoma. A phase II clinical trial of IT plus CPLI polio virotherapy is ongoing (NCT06177964). This study implicates the lymphatic system as a virotherapy target and demonstrates that CPLI virotherapy has the potential to complement brain tumor immunotherapy. See related Spotlight by Kaufman, p. 182.