IMPACT OF PROTON THERAPY ON DRAINING LYMPH NODES

Draining lymph nodes are important sites of immune response. They contain large numbers of T‐, B‐, and antigen‐presenting cells, which play crucial roles in tumor therapy. 44 , 45 , 46 , 47 During radiotherapy, immunogenic cell death and cytoplasmic DNA activate cGAS‐STING, which drives the recruitment and cross‐priming of dendritic cells in tumor‐draining lymph nodes. Subsequently, chemokines guide lymphocyte trafficking and expansion, ultimately leading to lymphocyte infiltration into tumors. 48 , 49 Irradiation of draining lymph nodes during radiotherapy may damage the immune system. For example, elective nodal irradiation (ENI) could reduce the expression of chemokines CXCR3 and CCR5, and inhibit the infiltration of IFNγ+/TNFα+ CD8+ T cells. 50 In head and neck tumors, ENI reduces the number of CD69+CD8+ and CCR7+CD4+ T cells in the blood. It also decreases the number of LFA‐1+CD44+CD4+ T cells in the draining lymph nodes and tumor microenvironment (TME). These changes suppress antitumor immunity, thereby increasing the risks of both local tumor recurrence and distant metastasis. 51 Notably, lymph node irradiation can also reduce the abscopal effect by inhibiting stem‐like CD8+ T‐cell proliferation within the tumor. 52 Proton therapy, which is characterized by reduced irradiation exposure of lymph node, preserves anti‐tumor immunity. Using a mouse model of glioblastoma (GBM), Pham et al. found that proton therapy can reduce radiation exposure to lymph nodes, thereby preserving specific T‐cell subsets, such as naive CD8+ T cells. 53 The effect of proton therapy on draining lymph nodes should be the focus of future studies, considering the limited number of studies.