Tumor-Draining Lymph Node-Targeted Electrochemotherapy: A Hypothesis for In Situ Cancer Vaccination.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy by enhancing T-cell-mediated anti-tumor responses in solid malignancies. However, their efficacy is often limited by tumor-specific factors, T-cell dysfunction in cold tumors, or in the presence of lymph node metastasis (LNM). Moreover, clinical trials indicate no significant survival advantage of sentinel lymph node biopsy (SLNB) over no lymph node surgery in early-stage cancers, highlighting the need for novel combinatorial approaches to improve treatment outcomes. Tumor electrochemotherapy (ECT) can overcome immunosuppressive barriers in the tumor microenvironment by applying high electric fields that create transient micropores in cell membranes. This allows the enhanced uptake of chemotherapeutic drugs, resulting in increased cytotoxicity and the release of damage-associated molecular patterns (DAMPs). This triggers immunogenic cell death (ICD), a process that signals immune cells to attack cancer and promotes tumor regression. Considering advancements in lymphatic-targeted therapies and the immunostimulatory potential of uninvolved tumor-draining lymph nodes (TDLNs), TDLN-targeted ECT may act as an in situ cancer vaccination, activating immune cells within TDLNs through the release of DAMPs and serving as a hub to orchestrate systemic anti-tumor immunity. In patients with negative preoperative lymph node assessments, this approach may preserve lymph node integrity and lymphatic drainage while eradicating tumor cell colonies. When applied as neoadjuvant therapy before any TDLN treatment, TDLN-targeted ECT may leverage higher tumor-associated antigen loads, foster persistent immune memory, and reduce the risk of post-operative immune evasion.