Abstract 4480: Novel targeting API@API nanomedicines for synergistic molecular signaling modulation in head and neck cancer and the microenvironment

Head and neck cancer (HNC) has become a prominent health concern in Taiwan, particularly among young males, with rising socioeconomic implications due to traditional treatments’ limited success in preventing recurrence and metastasis. Our study introduces a novel API@API nanoformulation strategy that combines multiple active pharmaceutical ingredients (APIs) to synergistically target signaling pathways, aiming to overcome limitations of current HNC therapies and reduce toxicity. The API@API nanoformulation leverages natural nanoparticles derived from Cordyceps sinensis, incorporating key drugs such as FTY720 and Perifosine. The formulation optimizes amphipathic drug properties, allowing for higher bioavailability and targeted therapeutic action. By evaluating API@API nano cocktails in preclinical HNC models, we observed increased efficacy, with enhanced cytotoxicity and downregulation of critical pathways in HNC cells. The formulation demonstrated selective cytotoxicity across cancer stages, effectively targeting the tumor microenvironment (TME) through dual-drug-loaded nanoparticles. We also accessed the in vitro and in vivo efficacy of API@API nano cocktails in suppressing tumor growth, modulating immune responses, and reducing cancer cell migration. The platform demonstrated improved pharmacokinetics, enhanced tumor accumulation, and prolonged retention at tumor sites. Further immunological analyses indicated an immunosuppressive-to-immunomodulatory shift within the TME, with increased dendritic and M1 macrophage activity and reduced immunosuppressive cell populations. Spatial proteomic analyses confirmed enhanced immune cell distribution with reducing tumor associate neutrophiles, indicating that API@API formulations may improve HNC sensitivity to immunotherapy. In conclusion, the API@API nanoformulation platform has shown potential as an effective therapeutic strategy for HNC, offering significant advantages in efficacy, reduced side effects, and TME modulation. This platform supports broader biopharmaceutical applications, aligning with the global need for advanced cancer treatments. Citation Format: Li-Xing Yang, Ru-Fen Chen, Yan-Wei Wu, Pei-Wen Wang, Chih-Chia Huang, Dar-Bin Shieh. Novel targeting API@API nanomedicines for synergistic molecular signaling modulation in head and neck cancer and the microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4480.