Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.

Inflammation is a hallmark of cancer 1 . In cancer patients, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio (NLR), associates with shorter survival and treatment resistance across malignancies and therapeutic modalities 2-5 . Whether myeloid inflammation drives prostate cancer progression in humans remain unclear. Herein we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients. We show that higher blood NLR reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species including myeloid chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel androgen receptor signaling inhibitor (ARSI) resistance, and if inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with ARSI-resistant mCRPC. This combination was well tolerated without dose-limiting toxicity and decreased circulating neutrophils, reduced intratumor CD11b + HLA-DR lo CD15 + CD14 - myeloid cell infiltration, and imparted durable clinical benefit with biochemical and radiological responses in a subset of mCRPC patients. This study provides the first clinical evidence that senescence-associated myeloid inflammation can fuel mCRPC progression and resistance to AR blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.