Structural vulnerabilities of the breast tumor-draining lymph node to radiotherapy-induced fibrosis and lymphedema risk

Lymphedema is a significant survivorship burden in breast cancer, associated with chronic morbidity, diminished quality of life, and increased susceptibility to locoregional recurrence. Radiotherapy to the axillary lymph node, the principal drainage and immune-surveillance hub for the breast, is the dominant late driver of this condition, producing lymphocyte loss, stromal injury, and progressive fibrosis that restricts normal lymphatic flow. Yet the specific intranodal structures that fail first under radiotherapy stress, and how their collapse contributes to impaired antitumor immunity, remain unclear. To date, direct experimental resolution is limited, as lymph nodes cannot be repeatedly imaged after radiotherapy, and existing animal studies lack the spatial resolution and sex-specific depth needed to map structural collapse. This challenge is further compounded by the lymph node's highly nonlinear stromal-sinus architecture, where even small disruptions can propagate unpredictably across the transport network, making computational modeling essential. To address this gap, we developed an agent-based model of the breast tumor-draining lymph node that integrates established fibroblastic reticular cell microanatomy with the broader sinus architecture. To our knowledge, this is the first structural model capable of identifying radiotherapy-induced failure modes within the draining lymph node. Radiotherapy injury was modeled as progressive fibrosis, introducing targeted removal of stromal-sinus connections, local increases in flow resistance, and reduced HEV-paracortex communication based on published radiotherapy injury profiles. Across injury scenarios, radiotherapy consistently produced early nonuniform disruption at stromal-sinus junctions that serve as conduits for lymph inflow and immune-cell entry. Loss of these regions impaired drainage, prolonged antigen transit, and reduced T-cell delivery to antigen-rich compartments, revealing a selective degradation of the LN's core transport axis. Together, these failures define a reproducible intranodal “collapse axis” whose breakdown forecasts diminished antitumor surveillance and generates a radiotherapy immune-risk map that pinpoints the pathways most vulnerable to fibrotic injury. These insights represent a paradigm shift toward structure-guided radiotherapy planning, enabling lymph-node-sparing treatment strategies, more precise recurrence-risk stratification, and targeted interventions to prevent chronic morbidity in breast cancer survivors.