PO.TB10.05 · 肿瘤生物学
乳酸驱动的胆固醇重编程诱导衰老胰腺癌中的成纤维细胞衰老和免疫抑制
Lactate-driven cholesterol reprogramming induces fibroblast senescence and immune suppression in aged pancreatic cancer
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摘要 Abstract
中文摘要
背景：衰老深刻重塑胰腺肿瘤微环境（TME），其中衰老癌症相关成纤维细胞（senCAF）积累并促进肿瘤进展。然而，衰老肿瘤细胞产生的、诱导成纤维细胞衰老并介导免疫抑制的代谢线索仍知之甚少。
方法：结合多重免疫荧光（mIF），对小鼠和人单细胞RNA测序数据集进行整合分析，揭示了衰老胰腺导管腺癌（PDAC）中p16⁺ senCAF的显著富集。靶向代谢组学和同位素示踪鉴定乳酸为驱动成纤维细胞衰老的关键代谢物。采用乳酰化蛋白质组学、ATAC-seq、CUT&Tag和定点突变来确定功能性乳酰化位点。多重细胞因子谱分析鉴定调节免疫抑制性微环境的senCAF分泌组。
结果：衰老PDAC表现出senCAF的显著扩增，经scRNA-seq和mIF验证。代谢组学和同位素示踪分析显示，衰老肿瘤细胞分泌的乳酸通过上调的MCT1转运体优先被成纤维细胞摄取，触发代谢和表型衰老。蛋白质组学分析鉴定出增强的组蛋白A-蛋白乳酰化（H3K18la）作为一种关键的衰老相关修饰，与不良预后强相关。乳酰化位点突变（K18R）恢复了成纤维细胞的增殖能力并减少SASP分泌。机制上，组蛋白乳酰化通过转录激活SQLE（角鲨烯环氧化酶，胆固醇生物合成中的限速酶）重编程胆固醇代谢。胆固醇积累进一步强化成纤维细胞衰老并维持炎症性SASP信号（包括IL-8、CXCL12和TGF-beta），建立免疫抑制性肿瘤微环境。药理学抑制SQLE或阻断乳酸摄取显著减少senCAF积累、恢复CD8⁺ T细胞浸润，并改善衰老PDAC模型的生存。
结论：衰老PDAC细胞通过乳酸驱动的组蛋白乳酰化对成纤维细胞进行代谢重编程，重新激活胆固醇生物合成并维持衰老。这一代谢-表观遗传轴助长免疫抑制和肿瘤进展。靶向乳酸-H3K18la-SQLE通路为重编程衰老肿瘤间质并增强PDAC抗肿瘤免疫提供了一种有前景的治疗策略。
查看英文原文 English abstract
Background: Aging profoundly remodels the pancreatic tumor microenvironment (TME), where senescent cancer-associated fibroblasts (senCAFs) accumulate and promote tumor progression. However, the metabolic cues derived from aged tumor cells that induce fibroblast senescence and mediate immune suppression remain poorly understood.
Methods: Integrated analyses of murine and human single-cell RNA-sequencing datasets combined with multiplex immunofluorescence (mIF) revealed a marked enrichment of p16⁺ senCAFs in aged pancreatic ductal adenocarcinoma (PDAC). Targeted metabolomics and isotope tracing identified lactate as a key metabolite driving fibroblast senescence. Lactyl-proteomics, ATAC-seq, CUT&Tag, and site-directed mutagenesis were used to define functional lactylation sites. Multiplex cytokine profiling identifies the secretome of senCAFs that modulates the immunosuppressive microenvironment.
Results: Aged PDAC exhibited a marked expansion of senCAFs, validated by scRNA-seq and mIF. Metabolomic and isotope-tracing analyses revealed that lactate secreted by aged tumor cells was preferentially imported by fibroblasts through upregulated MCT1 transporters, triggering metabolic and phenotypic senescence. Proteomic profiling identified enhanced histone A-protein lactylation (H3K18la) as a key senescence-associated modification strongly correlated with poor prognosis. Mutation of the lactylation site (K18R) restored fibroblast proliferative capacity and reduced SASP secretion. Mechanistically, histone lactylation reprogrammed cholesterol metabolism by transcriptionally activating SQLE (squalene epoxidase), a rate-limiting enzyme in cholesterol biosynthesis. Cholesterol accumulation further reinforced fibroblast senescence and sustained inflammatory SASP signaling, including IL-8, CXCL12, and TGF-beta, establishing an immunosuppressive tumor microenvironment. Pharmacologic inhibition of SQLE or blockade of lactate import markedly decreased senCAF accumulation, restored CD8⁺ T cell infiltration, and improved survival in aged PDAC models.
Conclusion: Aged PDAC cells metabolically reprogram fibroblasts via lactate-driven histone lactylation, reactivating cholesterol biosynthesis and maintaining senescence. This metabolic-epigenetic axis fuels immune suppression and tumor progression. Targeting the lactate-H3K18la-SQLE pathway offers a promising therapeutic strategy to reprogram the aged tumor stroma and enhance anti-tumor immunity in PDAC.
利益披露 Disclosure
Z. Tu, None..
S. Zhu, None..
Y. Chen, None.