LAMP1 enhances DNA-PKcs-mediated AKT phosphorylation and VEGFC secretion to promote lymph node metastasis in esophageal squamous cell carcinoma.

Lymph node metastasis (LNM) is a major determinant of poor prognosis in esophageal squamous cell carcinoma (ESCC), with patients remaining at high risk of postoperative recurrence in the absence of reliable predictors or effective interventions. To address this unmet clinical need, we perform proteomic and bioinformatic analyses and identify lysosome-associated membrane protein 1 (LAMP1) as a critical driver of LNM in ESCC. LAMP1 is markedly overexpressed in primary tumors that with LNM and correlates with worse survival outcomes across independent cohorts. Gain- and loss-of-function experiments demonstrate that LAMP1 promotes lymphangiogenesis and lymphatic metastasis both in vitro and in vivo. Mechanistically, LAMP1 interacts with DNA-PKcs, mediates AKT activation, leading to VEGFC upregulation and secretion, thereby driving lymphangiogenesis and metastasis. Importantly, treatment with the LAMP1 inhibitor Parishin C significantly suppresses LNM in preclinical ESCC models. These findings uncover a previously unrecognized LAMP1/DNA-PKcs/AKT/VEGFC signaling axis that promotes ESCC progression and highlight LAMP1 as a promising biomarker and therapeutic target for preventing LNM and improving patient outcomes.