Targeting cysteinyl leukotriene receptor 1 reprograms tumor-promoting myelopoiesis and overcomes immune checkpoint therapy resistance.

'Emergency' myelopoiesis usually occurs to facilitate malignancy progression. Immunosuppressive neutrophils, also termed polymorphonuclear myeloid-derived suppressor cells, are potent mediators of immunosuppression and tumor promotion. Here we demonstrate that the STAT3-dependent induction of cysteinyl leukotriene receptor 1 (CysLTR1), with a key role in asthma and other inflammatory conditions, sustains tumor-promoting emergency myelopoiesis. Genetic ablation and pharmacological inhibition of CysLTR1 diminishes tumor growth with enhanced antitumor immunity. Antitumor effect of CysLTR1 inhibition is linked with transcriptomic rewiring of granulopoiesis and neutrophil reprogramming toward an antitumor immune phenotype; this process requires the distinct transcriptional factors MXD1 and NFE2 to specifically dictate myeloid progenitor commitment and differentiation in association with controlled de novo synthesis of granule cargoes. Targeting CysLTR1 with clinically available antagonists overcomes resistance to anti-PD1 in multiple mouse tumor models. These findings, thus, open the opportunity for rapid translation of CysLTR1 inhibitors targeting emergency granulopoiesis and unveil a new programmed 'disarming' neutrophil strategy to improve cancer immunotherapy.