# The Lymphatic–Bone Axis in Cancer Metastasis

## TL;DR

This review explains how lymph nodes help cancer cells prepare to spread to bones, challenging old ideas and suggesting new treatment strategies.

## Contribution

Introduces the Lymphatic–Bone Axis as a novel framework explaining how lymph nodes actively prime cancer cells for bone metastasis.

## Key findings

- Lymph nodes act as 'evolutionary gateways' that modify cancer cells to survive in bone environments.
- Cancer cells can bypass traditional routes and enter the bloodstream directly from lymph nodes via high endothelial venules.
- Therapies targeting only bone may be ineffective if cancer cells are already conditioned in lymph nodes.

## Abstract

Bone metastasis is a fatal complication of cancer that causes fractures and severe pain. Historically, it was thought that cancer cells reached bones solely through the bloodstream. However, patients with lymph node metastases are at high risk for bone lesions, yet surgical removal of these nodes often fails to prevent further spread. This suggests that lymph nodes function as more than passive filters; they may actively modify cancer cells to survive in the bone environment. This review introduces the Lymphatic–Bone Axis, describing how the lymph node environment alters cancer cells to express specific bone-homing proteins and acquire bone-like traits. We also discuss evidence that cancer cells can enter the bloodstream directly from lymph nodes through specialized blood vessels, bypassing standard routes. These insights suggest that new treatments should target these adaptive processes within the lymphatic system before cancer cells colonize bone.

Bone metastasis is a devastating complication of advanced osteotropic malignancies, notably breast, prostate, lung carcinomas, and malignant melanoma, and remains a primary driver of mortality. Historical paradigms have conceptualized skeletal dissemination almost exclusively as a hematogenous process wherein circulating tumor cells colonize receptive bone marrow niches. However, this model fails to reconcile why lymph node metastasis consistently serves as a potent predictor of bone involvement even though therapeutic lymphadenectomy rarely prevents distant spread. This discordance suggests that lymph nodes function not merely as passive reservoirs but as active ‘evolutionary gateways’ that sculpt bone-tropic metastatic clones. In this review, we introduce the Lymphatic–Bone Axis, a framework integrating lymphatic biology into models of bone metastasis. We synthesize emerging evidence elucidating how the lymph node microenvironment primes tumor cells through CCR7-CXCR4 switching, induction of osteomimicry programs, and metabolic reprogramming that favors survival within the bone marrow. We also discuss preclinical data demonstrating direct intranodal intravasation via high endothelial venules (HEVs), providing a rapid route into the systemic circulation that bypasses the thoracic duct. Beyond consolidating current knowledge, we outline a research agenda for dissecting this axis, including longitudinal single-cell transcriptomic mapping and functional assessments of lymph node-derived tumor cells. Finally, we consider translational implications, highlighting why bone-targeted agents alone may prove insufficient once cells are conditioned within lymphatic niches. By mechanistically linking lymphatic priming to skeletal colonization, this review informs the rational design of multimodal therapeutic approaches that jointly target lymphatic transit and the bone microenvironment.