Cancer-associated fibroblasts in lymph node metastasis: Insights and therapeutic strategies

Lymph node metastasis (LNM) represents a critical dissemination route for many malignancies, profoundly influencing patient prognosis through its role in driving disease progression and recurrence. This metastatic cascade involves tumor cell invasion into lymphatic structures, where the complex interactions within the tumor microenvironment (TME) facilitate further dissemination to distant sites. Among TME components, cancer-associated fibroblasts (CAFs) have emerged as pivotal regulators in disease progression and metastatic spread by orchestrating dynamic crosstalk between malignant cells and stromal networks. Mounting evidence highlights the multifaceted contributions of CAFs to LNM pathogenesis, particularly their capacity to prime metastatic niches and enable tumor cell intravasation into lymphatic vessels. This review systematically examines the molecular and functional mechanisms through which CAFs promote LNM, focusing on their dual roles in establishing pre-metastatic niches and facilitating lymphovascular invasion by tumor cells. By synthesizing recent advances in CAF biology and LNM pathophysiology, this review aims to deepen the mechanistic understanding of metastatic dissemination while identifying potential therapeutic opportunities for clinical translation.