Immune remodeling of tumor-draining lymph nodes: mechanistic determinants of checkpoint blockade responsiveness

Abstract

Remodeling of tumor-draining lymph nodes (tdLNs) can precede overt nodal metastasis and has emerged as a determinant of immune checkpoint blockade (ICB) responsiveness. Sustained lymphatic delivery of tumor-derived antigens, extracellular vesicles, cytokines, and metabolites perturbs stromal and vascular programs, including lymphatic expansion, high endothelial venule dysfunction, and disruption of fibroblastic reticular cell (FRC) networks, with downstream impairment of antigen presentation and T-cell priming. Metabolites such as lactate and adenosine further promote tolerogenic antigen-presenting cell states and increase the activation requirements of tumor-reactive T cells. These changes are predicted to reduce the availability of TCF1+ progenitor-exhausted CD8+ T cells (Tpex), an ICB-responsive reservoir that sustains clonal expansion during PD-1/PD-L1 blockade. The Review links tdLN structural, cellular, and metabolic remodeling to ICB response and resistance, highlights reinforcement of regulatory circuits after metastatic colonization, and discusses translational strategies that incorporate tdLN functional state into therapeutic design, including restoration of type 1 conventional DC (cDC1) competence, metabolic co-targeting, neoadjuvant sequencing, adoptive use of tdLN-derived T cells, and biomarker-guided planning of local therapies.