口腔鱗狀細胞癌每年全球約有39萬個新發病例，五年整體存活率不到50%。目前以順鉑合併放射療法為主要治療方式，然而順鉑嚴重的系統性毒性、耐藥性，以及傳統放化療對腫瘤免疫微環境調控有限，使整體治療效果受到限制。因此，本研究設計並合成標靶性奈米藥物Au@PSMA@Cisplatin-Fucoidan，以pH敏感性苯乙烯馬來酸酐共聚物（PSMA）負載順鉑、奈米金提供放射增敏效果，並以褐藻醣膠進行P-selectin蛋白標靶修飾，結合放射療法與抗PD-L1抗體，探討三聯療法對口腔鱗狀細胞癌的抗腫瘤功效、分子死亡機制與腫瘤免疫微環境調控。
奈米藥物由實驗室自行合成，物化特性分析確認水合粒徑為122.4奈米（PDI 0.197），界面電位為-49.3毫伏，並具備pH敏感性藥物釋放能力（pH 5.5下24小時釋放率約63%，pH 7.4約17%）。體外細胞實驗使用MOC-L1細胞，體內實驗則以C57BL/6小鼠建立同系皮下腫瘤模型，透過IVIS活體影像評估生物分布，並以流式細胞儀分析腫瘤免疫細胞組成。
細胞實驗結果顯示，25 ppm奈米藥物合併6 Gy放射線使MOC-L1細胞存活率降至約42%，並同時活化細胞凋亡、自噬通量與鐵死亡路徑。動物實驗結果方面，三聯療法組的腫瘤內CD8+細胞毒性T淋巴球浸潤率顯著高於各對照組（p=0.015），並伴隨CD8+ T細胞效應記憶表型的活化與樹突細胞-CD8+細胞正相關（r=0.6，p=0.002）。然而，各組腫瘤體積未達統計顯著差異，原因可能與MOC-L1皮下腫瘤模型的生長異質性及同系動物間免疫系統的個體變異性有關。
本研究結果為三聯療法策略應用於口腔鱗狀細胞癌提供了初步的機制依據。未來研究應進一步量化順鉑實際載藥量與腫瘤部位釋放量，並與臨床用藥劑量進行比對，同時納入肝腎毒性檢測指標、優化奈米藥物注射次數與放射治療分次方案，並以更大樣本量進一步驗證其治療潛力。

Oral squamous cell carcinoma (OSCC) carries a five-year overall survival rate below 50%, and conventional cisplatin-based chemoradiotherapy is limited by systemic drug toxicity, resistance, and an immunosuppressive tumor immune microenvironment. This study designed and synthesized Au@PSMA@Cisplatin-Fucoidan, a targeted nanoparticle incorporating pH-responsive PSMA for cisplatin loading, gold nanoparticles for radiosensitisation, and fucoidan for P-selectin-directed tumor vascular targeting, and evaluated the trimodal combination with radiotherapy and anti-PD-L1 checkpoint blockade in a syngeneic murine OSCC model.
Physicochemical characterization confirmed a hydrodynamic diameter of 122.4 nm, zeta potential of −49.3 mV, and pH-responsive cisplatin release (~63% at pH 5.5 vs ~17% at pH 7.4). In vitro, combined NP+RT (25 ppm + 6 Gy) reduced MOC-L1 viability to ~42% with synergistic cytotoxicity, activating intrinsic apoptosis, autophagic flux, and ferroptosis through complementary downregulation of GPX4 (by NP) and xCT (by IR). In vivo, the triple combination achieved the highest intratumoral CD8+ cytotoxic T lymphocyte infiltration (one-way ANOVA, p = 0.015), accompanied by a central-to-effector memory CD8+ T cell phenotypic shift and a significant DC–CD8 positive correlation (r = 0.57, p = 0.004), supporting an ICD-driven antigen presentation axis. Tumor volume differences did not reach statistical significance, might be attributed to the inherent growth heterogeneity of MOC-L1 and high inter-individual immune variability in the syngeneic model.
These findings provide a mechanistic rationale for the trimodal NP+RT+anti-PD-L1 strategy in OSCC. Future work should prioritize quantification of cisplatin drug loading and intratumoral release relative to clinical dosing benchmarks, incorporation of hepatotoxicity indices, optimization of nanoparticle injection and radiation treatment schedules, and validation in larger cohorts.

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