中国科学院分子细胞科学卓越创新中心王广川小组在研究中取得进展。他们探明了CLIM-TIME鉴定转移性微环境调节剂对T细胞治疗反应。该项研究成果发表在2026年2月11日出版的《细胞》上。
该研究团队介绍了肿瘤免疫微环境（CLIM-TIME）的CRISPR激光捕获微解剖（LCM）整合图谱，这是一个可扩展的平台，将CRISPR筛选与转移性肿瘤的LCM整合在一起，进行转录组学、反褶积和免疫荧光分析。CLIM-TIME使肿瘤抑制基因（TSG）丢失如何重塑TME和调节免疫反应的空间分辨映射成为可能。课题组人员鉴定了7种不同的TME亚型，揭示了DNA修复和Polycomb抑制复合体（PRC） TSG丢失与免疫浸润性TME对T细胞治疗敏感有关。相比之下，Hippo通路中TSGs的敲除通过培养细胞外基质（ECM）升高的骨髓富集但T细胞排斥的TMEs，促进免疫逃避和治疗抵抗。靶向ECM交联酶LOXL2可有效重塑转移性TME，增强T细胞浸润，提高多种癌症肺转移的治疗效果。
据了解，肿瘤微环境（TME）是有效免疫治疗的主要障碍，但高通量微扰映射方法来解剖TME空间复杂性及其上下文免疫调节剂仍然缺乏。
附：英文原文
Title: CLIM-TIME identifies metastatic microenvironment modulators for T cell therapy response
Author: Yinghua Wang, Weiwei Hu, Rui Xia, Xianfa Yang, Yange Gu, Zihan Ning, Tiange Yang, Chune Yu, Lulu Zhang, Dun Li, Yitian Jin, Jianhua Li, Feifei Zhang, Yaochen Xu, Chenqi Xu, Zhengxin Wang, Naihe Jing, Luonan Chen, Guangchuan Wang
Issue&Volume: 2026-02-11
Abstract: The tumor microenvironment (TME) poses a major barrier to effective immunotherapy, yet high-throughput perturbation-mapping approaches to dissect TME spatial complexity and its contextual immune modulators remain lacking. Here, we introduce CRISPR-laser-captured microdissection (LCM) integration mapping of the tumor-immune microenvironment (CLIM-TIME), a scalable platform that integrates CRISPR screening with LCM of metastatic tumors for transcriptomic, deconvolution, and immunofluorescence analyses. CLIM-TIME enables spatially resolved mapping of how tumor suppressor gene (TSG) loss reshapes the TME and modulates immune responses. We identified seven distinct TME subtypes, revealing that DNA repair and Polycomb repressive complex (PRC) TSG loss is linked to immune-infiltrated TMEs sensitive to T cell therapy. In contrast, knockouts of TSGs in the Hippo pathway promoted immune evasion and therapy resistance by fostering myeloid-enriched but T cell-excluded TMEs with elevated extracellular matrix (ECM). Targeting the ECM-crosslinking enzyme LOXL2 effectively remodeled the metastatic TME, enhancing T cell infiltration and improving therapeutic efficacy in lung metastases across multiple cancers.
DOI: 10.1016/j.cell.2025.12.042
Source:https://www.cell.com/cell/abstract/S0092-8674(25)01491-6