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Concurrent P-Selectin Targeting Nanoparticle Orchestrates Tumor-Immune Dynamics for Advanced Immunochemotherapy
Wei Lee1, Syuan-Ling Lin2,3, Jui-Yu Chen2
1Cell Therapy Center, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan.
Abstract:
Cancer therapy is often constrained by targeting single pathogenic mechanisms without addressing the complex tumor microenvironment (TME). Here, we introduce FINAL (Fucoidan-docetaxel Immunomodulatory Nanoparticles as an Antitumoral Lancer), a surface-engineered nanoplatform that simultaneously targets P-selectin-expressing cancer cells and tumor-associated macrophages (TAMs). Beyond targeting specificity, fucoidan surface modification provides intrinsic bioactivities that individually modulate both cell types while coordinately reshaping the TME. FINAL achieves dual-cell orchestration through P-selectin-mediated targeting, activating both receptor-dependent signaling pathways and receptor-independent bioactivities of fucoidan and DTX. P-selectin-mediated targeting enhances cellular uptake and disrupts tumor-TAM adhesion, reducing the level of circulating hybrid cell (CHC) formation. Independent of targeting, fucoidan's bioactivity reduces cellular reactive oxygen species in cancer cells, promotes M1 macrophage polarization, and suppresses VEGF-A-mediated angiogenesis. RNA-seq transcriptomic profiling demonstrated that FINAL drives synergistic immune activation pathways while simultaneously repressing tumor progression signatures, providing mechanistic evidence for concurrent tumor-immune dynamics at the molecular level. In triple-negative breast cancer (TNBC) models, this system-level approach achieved breakthrough therapeutic outcomes, including doubling survival duration, suppressing primary tumor growth, inhibiting lung metastasis, and preserving bone marrow hematopoietic function, demonstrating translational potential compared to conventional docetaxel formulations. Importantly, FINAL maintained therapeutic benefits while reducing systemic toxicity, establishing an optimal balance between antitumor efficacy and safety. The rationally designed fucoidan nanobio interface establishes FINAL as a versatile platform for P-selectin-expressing diseases for next-generation immunochemotherapy agents with broad translational potential across multiple cancer types.
Insights
This study introduces FINAL, a novel nanoplatform that targets cancer cells and macrophages to improve triple-negative breast cancer therapy. FINAL enhances survival and reduces toxicity by modulating the tumor microenvironment.
Area of Science:
- Nanotechnology
- Cancer Biology
- Immunotherapy
Background:
- Current cancer therapies often fail to address the complex tumor microenvironment (TME).
- Targeting single mechanisms overlooks the intricate interactions within the TME.
- Developing novel strategies to simultaneously target cancer cells and immune cells is crucial for effective therapy.
Purpose of the Study:
- To introduce FINAL (Fucoidan-docetaxel Immunomodulatory Nanoparticles as an Antitumoral Lancer), a nanoplatform for simultaneous targeting of P-selectin-expressing cancer cells and tumor-associated macrophages (TAMs).
- To investigate the therapeutic potential of FINAL in reshaping the TME and enhancing cancer treatment outcomes.
- To evaluate the safety and efficacy of FINAL compared to conventional docetaxel formulations.
Main Methods:
- Surface-engineered nanoparticles (FINAL) were developed with fucoidan and docetaxel.
- P-selectin-mediated targeting was employed to engage cancer cells and TAMs.
- RNA-seq transcriptomic profiling was used to analyze molecular-level changes in tumor-immune dynamics.
- In vivo studies in triple-negative breast cancer (TNBC) models were conducted to assess therapeutic outcomes and toxicity.
Main Results:
- FINAL demonstrated dual-cell orchestration via P-selectin-mediated targeting, enhancing cellular uptake and disrupting tumor-TAM adhesion.
- Fucoidan's intrinsic bioactivities reduced cancer cell reactive oxygen species, promoted M1 macrophage polarization, and suppressed angiogenesis.
- Transcriptomic analysis revealed synergistic immune activation and repressed tumor progression signatures.
- In TNBC models, FINAL doubled survival duration, suppressed tumor growth, inhibited metastasis, and preserved bone marrow function.
- FINAL achieved significant therapeutic benefits with reduced systemic toxicity.
Conclusions:
- FINAL represents a versatile platform for P-selectin-expressing diseases, offering a next-generation immunochemotherapy approach.
- The system-level modulation of the TME by FINAL provides breakthrough therapeutic outcomes with improved safety.
- This nanoplatform shows broad translational potential across multiple cancer types for enhanced antitumor efficacy and reduced systemic toxicity.
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