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논문분류	춘계학술대회 초록집
제목	The Study on the Effects and Mechanisms of Nano-Drug Delivery System Targeting LTA4H in clear cell Renal Cancer Cells to Regulate Tumor Immune Microenvironment and Improve Immunotherapy Resistance
저자	Diaoyi Tan
출판정보	2026; 2026(1):
키워드	clear cell renal cell carcinoma, immunotherapy, cancer associated fibroblast
초록	Objectives: Clear cell renal cell carcinoma (ccRCC) is a common malignancy of the urinary system. Although immune checkpoint inhibitors (ICIs) are first-line therapies for advanced ccRCC, response rates remain limited due to the complex tumor immune microenvironment. Cancer-associated fibroblasts (CAFs) are critical regulators of this environment, but their role in ccRCC is not fully understood. Methods: Bioinformatic analyses were used to evaluate CAF infiltration and clinical significance in ccRCC. An arrayed metabolic enzyme–focused siRNA library was constructed to identify key regulators of CAF activation. In vitro and in vivo experiments were performed to investigate how LTA4H and its downstream metabolite LTB4 regulate CAF activation and modulate the immune microenvironment. Anti-CD70 antibody–modified Ubenimex-loaded liposomes were developed to selectively inhibit LTA4H in ccRCC tumor cells. Results: CAFs were enriched in ccRCC and correlated with poor prognosis. Screening identified LTA4H as a key driver of CAF activation. LTA4H knockdown suppressed tumor growth, reduced CAF abundance, increased CD8⁺ TILs, and enhanced ICI efficacy. LTB4 was elevated in ccRCC and associated with immunotherapy resistance and worse outcomes. Mechanistically, LTB4 binds BLT1, activates NF-κB and PI3K-AKT signaling, promotes CAF activation, and upregulates LGALS1 secretion. LGALS1 induces CD8⁺ TIL apoptosis and impairs cytotoxicity, weakening antitumor immunity. Conclusion: LTA4H-driven LTB4 production activates CAFs and induces LGALS1 secretion, leading to CD8⁺ TIL dysfunction and reduced ICI response in ccRCC. Targeted inhibition of LTA4H using anti-CD70 antibody–modified Ubenimex-loaded liposomes may enhance immunotherapy efficacy.
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