樹突細胞：連接先天與適應性免疫的橋樑

樹突細胞（dendritic cells, DCs）是免疫系統中的關鍵樞紐，負責連結先天免疫與適應性免疫反應。它們透過抗原呈現、釋放細胞激素與趨化激素，以及表達協同刺激分子，協調免疫系統的啟動與調節。樹突細胞不僅能維持免疫耐受性，防止自體免疫反應，也能活化效應細胞（effector cells），清除外來病原與異常細胞。

樹突細胞與疾病防治

由於樹突細胞具備卓越的抗原呈現能力，許多疫苗的設計目標即是活化樹突細胞，以促進免疫記憶的形成，保護人體免受病原感染。在癌症治療中，樹突細胞同樣扮演關鍵角色—除了利用腫瘤特異性的新抗原（neoantigen）進行免疫誘導外，直接活化 DC 以啟動免疫系統的毒殺機制，更是提升癌症免疫療法效果的重要策略。

核心技術的突破：體內直接標靶樹突細胞

目前，FDA 已核准自體樹突細胞免疫療法，其流程包括：由病人外周血中分離單核球，體外誘導分化並活化為樹突細胞，經腫瘤抗原刺激後再回輸體內。雖具療效，但過程繁瑣、耗時且成本高昂，限制其臨床普及。

為克服這些挑戰，我們開發了「樹突細胞標靶胜肽（SP65）」技術，將其鑲嵌於脂質體（liposome）中，並搭配能活化 DC 的藥物—芳香烴受體（AhR）拮抗劑，形成具專一性之細胞傳遞藥物(如下圖)。此技術可直接在體內標靶 DC，無需體外操作。我們發現該藥物能促進 DC 分泌 IL-12，進而活化自然殺手細胞（NK cells）分泌 IFN-γ，增強腫瘤毒殺能力。在免疫檢查點抑制劑抗藥性癌症（immune checkpoint inhibitor-refractory cancer）的小鼠模型中，該治療可顯著抑制腫瘤生長、延長存活期，且未觀察到副作用，顯示其為極具潛力的新一代癌症免疫治療策略。 

技術延伸應用與未來潛力

傳統疫苗往往透過誘發局部發炎來活化免疫反應，因此接種部位容易出現紅腫疼痛，甚至造成全身性不適。而對免疫功能較低的族群，疫苗效果亦可能有限。SP65標靶胜肽可整合於多種藥物載體平台（如脂質奈米粒子），根據不同疾病需求包覆適當的抗原與佐劑，將藥物快速且精準地傳遞至樹突細胞。此策略不僅可降低施用劑量與副作用，還能在無需引發局部發炎的情況下直接活化免疫反應，展現出高度的疾病應用潛力。

此外，該技術也具備跨物種應用前景。許多動物傳染病，如豬瘟與禽流感，造成嚴重的農業損失。透過基因工程設計能主動將病原抗原傳遞至樹突細胞的酵母載體，可提升動物免疫力與防疫效果，開啟新世代動物疫苗的發展方向。

（113年度TBF學術講座、中研院生醫所　李永凌研究員）

Development of Dendritic Cell Targeted Liposomal Platform for Cancer Immunotherapy

Dendritic Cells: The Bridge Between Innate and Adaptive Immunity

Dendritic cells (DCs) serve as a pivotal bridge connecting the innate and adaptive immune systems. Through antigen presentation, secretion of cytokines and chemokines, and expression of co-stimulatory molecules, DCs coordinate the initiation and regulation of immune responses. They not only maintain immune tolerance to prevent autoimmune reactions but also activate effector cells to eliminate pathogens and abnormal cells. 

Dendritic Cells in Disease Prevention and Therapy

Owing to their exceptional antigen-presenting capacity, DCs are a key target in vaccine design. By activating DCs through optimized combinations of antigens and adjuvants, vaccines can elicit strong and long-lasting immune protection against pathogens. In cancer immunotherapy, DCs also play a crucial role. In addition to utilizing tumor-specific neoantigens to stimulate immune recognition, directly activating DCs to trigger cytotoxic immune mechanisms represents a powerful approach to enhance antitumor efficacy. 

Technological Breakthrough: Direct Targeting of Dendritic Cells In Vivo

The U.S. FDA has approved autologous dendritic cell–based immunotherapies, in which peripheral blood mononuclear cells are isolated from the patient, differentiated and activated into DCs ex vivo, stimulated with tumor antigens, and then reinfused into the patient. Although effective, this process is labor-intensive, time-consuming, costly, and limited in clinical scalability.

To overcome these challenges, we developed a dendritic cell–targeting peptide (SP65) technology, incorporated into liposomal formulations and combined with an aryl hydrocarbon receptor (AhR) antagonist, a DC-activating compound (Panel). This innovation enables direct in vivo targeting of DCs without the need for ex vivo manipulation. Our studies show that this formulation enhances IL-12 secretion by DCs, stimulates natural killer (NK) cells to produce IFN-γ, and promotes their tumor-killing activity. In murine models of immune checkpoint inhibitor–refractory cancer, the treatment significantly suppressed tumor growth and prolonged survival without detectable side effects—demonstrating strong potential as a next-generation cancer immunotherapy.

Broader Applications and Future Potential

Conventional vaccines often rely on local inflammation at the injection site to create an activated immune microenvironment, which may cause pain, redness, or systemic discomfort. For immunocompromised individuals, insufficient immune activation can also limit vaccine efficacy. The SP65 peptide can be integrated into various delivery platforms, such as lipid nanoparticles (LNPs), to encapsulate disease-specific antigens or adjuvants and efficiently deliver them to DCs. This approach enables precise and rapid immune activation without inducing local inflammation, reduces the required drug dose, and minimizes adverse effects—offering a promising path toward safer and more effective immunotherapies.

Beyond human medicine, this technology also holds potential in veterinary applications. Infectious diseases such as classical swine fever and avian influenza cause major agricultural losses worldwide. Using genetic engineering, we can design yeast-based delivery systems capable of transferring pathogen-derived antigens directly to DCs, thereby enhancing immune protection in animals and contributing to infectious disease control in livestock.

(2024 TBF Chair in Biotechnology, Professor Yungling Leo Lee)