International immunopharmacologyJul 31, 2026

Live CRISPR screening finds LTA4H may boost immunotherapy by affecting LTB4-driven neutrophil response

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 3, 2026

Abstract

LTA4H ablation was associated with enhanced PD-1 responsiveness in tumor models.

Leukotriene A4 hydrolase (LTA4H) was identified as a potential regulator of PD-1 resistance.
Increased infiltration and function of CD8+ T and NK cells were observed with Lta4h ablation.
Reduced accumulation of myeloid cells was linked to LTA4H ablation.
LTA4H expression was found in both malignant and myeloid cell compartments.
High levels of LTA4H in tumors correlated with myeloid-enriched areas and TGF-β related signaling.
Pharmacological blockade of LTB4 receptor signaling improved tumor control when combined with PD-1 blockade.

Simplified

Despite the clinical success of PD-1 blockade, therapeutic resistance remains a major barrier. Using an in vivo CRISPR-Cas9 screen with a metabolism-focused sgRNA library in MC38 and B16 syngeneic tumor models, we identified leukotriene A4 hydrolase (LTA4H) as a candidate regulator of PD-1 resistance. Lta4h ablation was associated with enhanced PD-1 responsiveness, increased CD8+ T and NK-cell infiltration and function, and reduced myeloid accumulation. Single-cell and spatial transcriptomic analyses showed that LTA4H is expressed in both malignant and myeloid compartments, with LTA4H-high tumor regions associated with myeloid-enriched niches and TGF-β related signaling. Mechanistically, hypoxia-induced HIF1α upregulated Lta4h in tumor cells, supporting tumor cells as one relevant source of LTA4H/LTB4. LTA4H-LTB4 signaling was linked to myeloid remodeling and TGF-β1 production in LTB4-conditioned neutrophils. Pharmacological blockade of LTB4 receptor signaling with the BLT1 antagonist CP-105696 improved tumor control in combination with PD-1 blockade. These findings identify intratumoral LTA4H-LTB4 signaling as a metabolic-immune pathway associated with suppressive myeloid remodeling and support further investigation of LTB4 receptor blockade to improve PD-1 blockade responses.