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Targeting Lymphatic Function to Enhance Anti-Tumor Immunity and Suppress Metastasis
Xizhao Chen^*, Jinyeon Shin, Gopika Ashokan, Annica Stull-Lane, Sarit Pal, Geoffrey Hespe, Babak J. Mehrara, Raghu Kataru
Surgery, Memorial Sloan Kettering Cancer Center, New York, NY

Background:
Lymphatic vessels are traditionally viewed as passive conduits for tumor metastasis, shaping surgical paradigms in oncologic and reconstructive practice. However, their role in anti-tumor immunity remains poorly defined. Lymphatic activation relies on VEGF-C-driven lymphangiogenesis, which may promote tumor progression. We hypothesized that enhancing lymphatic function"”independent of exogenous growth factors"”can reprogram the tumor microenvironment (TME) to promote anti-tumor immunity.
Methods:
We generated a lymphatic gain-of-function model (LEC^{PTEN−/−}) with inducible Flt4-CreERT2-mediated PTEN deletion in lymphatic endothelial cells (LECs), augmenting lymphatic proliferation and migration without exogenous VEGF-C administration. Tumor responses were evaluated with melanoma (B16F10) implantation. Lymphatic function, immune profiling, and tumor outcomes were assessed using confocal imaging, fluorescent tracer assays, and flow cytometry.
Results:
Enhanced lymphatic function led to rapid tumor regression and 100% survival (Fig. A). Tumor growth was abrogated with no evidence of distant metastasis. Improved lymphatic drainage reduced peritumoral edema (Fig. B) and enhanced dendritic cell trafficking to lymph nodes (Fig. C). The TME was reprogrammed, with decreased regulatory T cells (Fig. D) and expansion of tumor-infiltrating CD8+ T cells (Fig. E). Draining lymph nodes showed absence of metastatic burden (Fig. F). Mechanistically, functional lymphatics exhibited reduced immune checkpoint signaling and increased CCL21 expression, promoting T-cell recruitment. CD8+ T-cell depletion abrogated tumor control, confirming immune-mediated effects.
Conclusion:
Enhancing lymphatic function by reprogramming LECs drives potent anti-tumor immunity and prevents metastasis. These findings challenge the paradigm that lymphatics primarily facilitate tumor spread and instead establish functional lymphatics as key regulators of immune surveillance. This approach introduces a novel, lymphatic-targeted strategy with potential implications for immunotherapy and cancer treatment.
Models adjusted for BMI, tissue expander size, and axillary irradiation. OR > 1 indicates higher odds with early exchange.

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