Targeted CysLTR1 Blockade Rescues Myeloid-Mediated Resistance to Immune Checkpoint Inhibition in Solid Malignancies:...

Myeloid-driven inflammation contributes to resistance to immune checkpoint inhibitors (ICIs) in solid tumors, partly through neutrophil-mediated immunosuppressive mechanisms. Experimental evidence suggests cysteinyl leukotriene receptor 1 (CysLTR1) signaling promotes tumor-supportive myelopoiesis. We evaluated whether pharmacologic CysLTR1 blockade with montelukast could mitigate myeloid-mediated resistance to anti-PD-1 immunotherapy.

A triangulated translational framework was applied using 3 independent data sets. First, CYSLTR1 and ELANE transcript expression were analyzed in The Cancer Genome Atlas (TCGA; n=9907). Second, a propensity-matched emulated clinical trial was conducted in the Mount Sinai TriNetX network, comparing pembrolizumab plus montelukast versus pembrolizumab alone in advanced solid malignancies (n=70 per arm). Third, a negative-control analysis was performed in UK Biobank cancer patients (n=19,443) using multivariable Cox proportional hazards models.

High concurrent CYSLTR1 and ELANE expression was associated with significantly poorer long-term survival in TCGA (P<0.0001). In TriNetX, concurrent montelukast exposure was associated with improved overall survival during pembrolizumab treatment (HR=0.505; 95% CI: 0.256-0.995; P=0.0441). In the UK Biobank, baseline neutrophil-to-lymphocyte ratio independently predicted mortality, but montelukast showed no survival interaction (P=0.957), supporting immunotherapy-specific rather than generalized oncologic benefit.

CysLTR1 blockade with montelukast may represent a low-cost companion strategy to overcome myeloid-mediated ICI resistance. These findings support prospective validation of combined anti-PD-1 and anti-CysLTR1 therapy in advanced solid tumors.