Targeting tumor-draining lymph node to overcome resistance to cancer immunotherapy: an update

Immune checkpoint inhibitor (ICI) resistance often stems from intratumoral T cell dysfunction. This review focuses on both tumor-intrinsic and tumor-draining lymph node (TDLN)-centric resistance mechanisms. We detail how specific defects within TDLNs - such as impaired dendritic cell migration and the establishment of immunosuppressive niches - initiate and perpetuate systemic immune dysfunction, ultimately leading to ICI resistance. To counter these challenges, we summarize the following TDLN-targeted strategies: (1) remodeling the TDLN immunosuppressive microenvironment to restore effective antigen presentation; (2) expanding the pool of progenitor exhausted T (Tpex) cells, with a focus on their primary reservoir in TDLNs; and (3) developing adoptive cell therapies using TDLN-derived Tpex cells to generate a robust, personalized antitumor response. By repositioning TDLNs as a central therapeutic target, recent findings suggest strategies aiming to overcome resistance at its source and improve ICI clinical outcomes.