Cancer Immunol Res. 2025 Nov 21. doi: 10.1158/2326-6066.CIR-25-0756. Online ahead of print.

ABSTRACT

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. Here we identify type-I interferon (IFN-I) signaling in glioma-draining cervical lymph nodes as a mediator of IT polio virotherapy. Transient IFN-I signaling after IT administration was rescued by cervical perilymphatic infusion (CPLI) virotherapy, targeting cervical lymph nodes directly. Dual-site (IT+CPLI) virotherapy induced profound inflammatory reprogramming of cervical lymph nodes, enhanced viral RNA replication and IFN-I 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 2 clinical trial of IT+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.

PMID:41270238 | DOI:10.1158/2326-6066.CIR-25-0756