Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid structures

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-04-03 DOI:10.1016/j.ccell.2025.03.011

Zhonghui Tang, Yinqi Bai, Qi Fang, Yuchen Yuan, Qianwen Zeng, Shuling Chen, Tianyi Xu, Jianyu Chen, Li Tan, Chunqing Wang, Qian Li, Jinpei Lin, Zhuoxuan Yang, Xia Wu, Guowei Shi, Ji Wang, Changjun Yin, Jianping Guo, Shiping Liu, Sui Peng, Ming Kuang

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引用次数: 0

Abstract

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates found in numerous cancers, often linked to enhanced immunotherapy responses and better clinical outcomes. However, the factors driving TLS maturation are not fully understood. Using near single-cell spatial transcriptomic mapping, we comprehensively profile TLSs under various maturation stages and their microenvironment in hepatocellular carcinoma (HCC). Based on their developmental trajectories, we classify immature TLSs into two groups: conforming and deviating TLSs. Our findings indicate that conforming TLSs, similar to mature TLSs, possess a niche function for immunotherapy responses, while deviating TLSs do not. We discover that the tryptophan-enriched metabolic microenvironment shaped by malignant cells contributes to the deviation of TLS maturation. Inhibiting tryptophan metabolism promotes intratumoral TLS maturation and enhances tumor control, synergizing with anti-PD-1 treatments. Therefore, promoting TLS maturation represents a potential strategy to improve antitumor responses and immunotherapy outcomes.

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空间转录组学揭示了色氨酸代谢限制肿瘤内三级淋巴样结构的成熟

三级淋巴样结构（TLSs）是在许多癌症中发现的异位淋巴样聚集体，通常与增强的免疫治疗反应和更好的临床结果有关。然而，推动TLS成熟的因素还没有被完全理解。利用近单细胞空间转录组图谱，我们全面分析了肝细胞癌（HCC）中不同成熟阶段的TLSs及其微环境。根据其发展轨迹，我们将未成熟的tls分为两类：符合标准的tls和偏离标准的tls。我们的研究结果表明，与成熟的TLSs类似，符合的TLSs具有免疫治疗应答的生态位功能，而偏离的TLSs则没有。我们发现，恶性细胞形成的富含色氨酸的代谢微环境有助于TLS成熟的偏差。抑制色氨酸代谢促进肿瘤内TLS成熟，增强肿瘤控制，与抗pd -1治疗协同作用。因此，促进TLS成熟是提高抗肿瘤反应和免疫治疗结果的潜在策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.