Maximilian Seidl ^1* Nikolas Hendrik Stoecklein ^2* Dennis Jones ^3*

• ¹ Heinrich-Heine University and University Hospital of Düsseldorf, Düsseldorf, Düsseldorf, Germany
• ² Clinic for General, Visceral and Pediatric Surgery, University Hospital Düsseldorf, Düsseldorf, Germany, Düsseldorf, Germany
• ³ Department of Pathology & Laboratory Medicine, Chobanian & Avedisian School of Medicine, Boston, United States

ratio of the long to short axes of cancer-free TDLNs, were found to correlate with the presence of tumor-infiltrating lymphocytes (TILs) in the primary tumor and overall survival outcomes. Compelling data demonstrate that elongated nodes are predictive of fewer TILs, as well as poor overall survival and disease-free survival. In contrast, nodes with a more rounded shape may have better immune function, as they are associated with a higher presence of TILs. The study also adds to growing evidence that normal tissue in lymph nodes is progressively replaced by fat as individuals age, which may indicate a decline in nodal function (5). It would be valuable to explore whether magnetic resonance imaging used for breast cancer diagnosis could also predict patient prognosis and therapeutic response, based on lymph node adiposity and shape.Circulating naïve lymphocytes in the blood enter lymph nodes through high endothelial venules (HEV). In the paracortex, T cells engage with dendritic cells and are presented with cognate antigen for priming. HEVs in metastatic lymph nodes have previously shown to be impaired by secondary tumors (6). The study by Bravo et al. (7) examined metastatic lymph nodes and in some cases identified focal accumulations of dendritic cells and naive lymphocytes next to HEVs-a structure they termed Favoring Antigen-Presenting Structures (FAPS). These structures were associated with improved distant-metastasis free survival in melanoma patients receiving vaccination with tumor antigens. Notably, patients were vaccinated after the resection of metastatic lymph nodes. This suggests that metastatic nodes may retain residual function before resection and potentially influence primary tumor burden, as patients with abundant FAPs exhibited a low primary tumor burden. This finding also suggests that vaccination may be more effective in patients with minimal residual disease compared to those with advanced disease. Further, when examined from an immunological perspective, beyond merely assessing the presence or absence of metastases, such analysis could potentially inform responses to vaccination or immune checkpoint therapy. Yet, the observed vaccine responses following the removal of TDLNs align with recent findings suggesting that distant lymph nodes may compensate for the loss of TDLNs (8).Although the use of antitumoral immune therapies, such as PD-L1/PD-1 and CTLA4 checkpoint inhibition is becoming more common, it is still difficult to identify patients who will benefit from existing therapies, even within the same tumor type. Gaining a better understanding of the tumor-derived immunomodulation that occurs in draining lymph nodes is crucial to the development of effective immunotherapy strategies. Current therapeutic concepts are primarily based on the endpoint response of effector cells in tumors, while the critical role that TDLNs have on shaping this response has largely been neglected. The study by Piersiala et al. (9) highlights the prognostic value of checkpoint pathways and immune cell subsets within TDLNs, shedding light on their role in shaping outcomes in oral squamous cell carcinoma. Multivariate analysis revealed that elevated levels of FoxP3+CD4+ T regulatory cells (Tregs) and TIGIT+CD8+ T cells were strongly associated with worse disease-free survival. These findings reflect distinct but synergistic mechanisms of immune suppression: Tregs actively inhibit effector immune responses, while TIGIT+CD8+ T cells represent an exhausted cytotoxic subset with reduced anti-tumor activity. Moreover, increased expression of immune checkpoints, such as PD-1 and CTLA-4, on T cells within TDLNs was significantly associated with recurrence, highlighting a profoundly immunosuppressive microenvironment that promotes immune evasion. By characterizing these immune dynamics, Piersiala et al. (9) underscore the potential of targeting TDLNs to reinvigorate anti-tumor immunity and enhance immunotherapeutic outcomes. This work strengthens the case for TDLNs as pivotal players in tumor progression and immune modulation. Overall, the findings in this research topic provide supportive evidence for incorporating TDLN analysis into cancer management, paving the way for innovative strategies that disrupt immune suppression and improve patient survival.