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CLIM-TIME identifies metastatic microenvironment modulators for T cell therapy response.

Yinghua Wang1, Weiwei Hu1, Rui Xia2

  • 1Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 20031, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Cell
|February 12, 2026
PubMed
Summary
This summary is machine-generated.

This study introduces CLIM-TIME, a new method to map the tumor microenvironment (TME). It reveals how gene loss impacts immune cells, identifying targets like LOXL2 to improve cancer immunotherapy.

Keywords:
Hippo pathwayLOXL2T cell infiltrationT cell therapyextracellular matriximmunotherapymetastasisspatial CRISPRtumor microenvironmenttumor suppressor gene

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Area of Science:

  • Oncology
  • Immunology
  • Genomics

Background:

  • The tumor microenvironment (TME) is a key challenge for cancer immunotherapy effectiveness.
  • High-throughput methods to map TME complexity and immune modulators are needed.

Purpose of the Study:

  • To develop a scalable platform for spatially resolved mapping of the tumor-immune microenvironment.
  • To understand how tumor suppressor gene (TSG) loss affects TME and immune responses.

Main Methods:

  • CRISPR-laser-captured microdissection (LCM) integration mapping of the tumor-immune microenvironment (CLIM-TIME) platform.
  • Integration of CRISPR screening with LCM for transcriptomic, deconvolution, and immunofluorescence analyses.
  • Analysis of metastatic tumors to map TME subtypes and immune infiltration.

Main Results:

  • Identified seven distinct TME subtypes based on TSG loss.
  • DNA repair and Polycomb repressive complex (PRC) TSG loss correlated with immune-infiltrated TMEs responsive to T cell therapy.
  • Hippo pathway TSG loss led to immune evasion and therapy resistance via myeloid-enriched, T cell-excluded TMEs with increased extracellular matrix (ECM).
  • Targeting LOXL2 remodeled the TME, boosted T cell infiltration, and improved immunotherapy in lung metastases.

Conclusions:

  • CLIM-TIME provides a powerful tool to dissect TME spatial complexity and identify therapeutic vulnerabilities.
  • Understanding TSG-driven TME alterations is crucial for developing effective immunotherapies.
  • Targeting ECM components like LOXL2 offers a promising strategy to overcome immune evasion in metastatic cancers.