Reshaping Tumor-Lymph Node Immune Axis via Targeted Lymphatic Delivery of Dual-Functional Immune Modulator for Enhanced Cancer Immunotherapy.

The efficacy of cancer immunotherapy is often limited by the immunosuppressive tumor microenvironment (TME) and insufficient immune activation in tumor-draining lymph nodes (TDLN). Since the TME and TDLN form a dynamic axis crucial for tumor metastasis and resistance to immune checkpoint blockade, strategies that effectively modulate both sites are critical. Here, we present a dissolving microneedle (MN) system that generates nanomicelles (NMCs) for localized delivery of a newly identified dual-functional macrocyclic trichothecene, Roridin E (R.E). R.E induces cancer cell-autonomous secretion of IFN-β and immunogenic cancer cell death (ICD). Direct delivery of R.E to the TDLN via the MN platform reshapes the local immune landscape to suppress cancer while minimizing off-target toxicity. In a B16F10 melanoma model, MN-guided R.E. delivery significantly improved tumor control, reduced lung metastases, and extended overall survival. This approach provides a minimally invasive and effective strategy for integrating natural-product-based therapies with advanced drug delivery systems to target the TME-TDLN axis, thereby improving outcomes in metastatic cancer.