Spatial multiomics profiling reveals ZFP36-mediated immunometabolic reprogramming in bladder cancer

Area of Science:

• Oncology
• Immunology
• Metabolomics

Background:

• Bladder cancer (BLCA) presents significant therapeutic challenges due to its heterogeneity and immune evasion.
• Understanding the interplay between tumor metabolism and immune response is crucial for developing effective immunotherapies.

Purpose of the Study:

• To systematically characterize the metabolic and transcriptional landscapes of BLCA using spatial multiomics.
• To identify novel therapeutic targets for bladder cancer immunotherapy.

Main Methods:

• Spatial metabolomics and spatial transcriptomics were employed to analyze tumor heterogeneity.
• Zfp36 knockout mouse models (whole-body and T cell-specific) were used to investigate ZFP36 function.
• Analysis of patient data linked ZFP36 expression to clinical outcomes.

Main Results:

• Distinct metabolic and transcriptional profiles were identified across different BLCA regions, revealing immune-associated metabolic reprogramming.
• ZFP36 was identified as a key regulator; its knockout enhanced T cell activation and infiltration.
• Elevated ZFP36 expression correlated with poorer patient outcomes, as ZFP36 was found to inhibit T cell activation by degrading immune regulator mRNAs.
• Combination therapy of Zfp36 knockout and anti-PD-1 demonstrated synergistic antitumor effects.

Conclusions:

• The study uncovers critical immune-metabolic regulatory pathways in BLCA.
• ZFP36 inhibition represents a promising therapeutic strategy for bladder cancer, potentially enhancing anti-PD-1 therapy efficacy.