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SUMMARYMyeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genomic editing, we generated a mouse model that is deficient of all monocyte chemoattractant proteins (MCP). Using this strain, we effectively abolished monocyte infiltration in glioblastoma (GBM) and hepatocellular carcinoma (HCC) murine models, which were enriched for monocytes or neutrophils, respectively. Remarkably, eliminating monocyte chemoattraction invokes a significant compensatory neutrophil influx in GBM, but not in HCC. Single-cell RNA sequencing revealed that intratumoral neutrophils promoted proneural-to-mesenchymal transition in GBM, and supported tumor aggression by facilitating hypoxia response via TNF production. Importantly, genetic or pharmacological inhibiting neutrophil in HCC or qMCP-KO GBM extended the survival of tumor-bearing mice. Our findings emphasize the importance of targeting both monocytes and neutrophils simultaneously for cancer immunotherapy.In BriefEliminating monocyte chemoattraction invokes compensatory neutrophil influx in tumor, and vice versa, rendering current myeloid-targeted therapies ineffective. Using genetic and pharmacological approaches combined with novel mouse models of GBM and HCC, we provide credence advocating for combinational therapies aiming at inhibiting both monocytes and neutrophils simultaneously.Highlights•Blocking monocyte chemoattraction results in increased neutrophil infiltration.•Increased neutrophil recruitment induces GBM PN to MES transition.•Inhibiting neutrophil infiltration in monocyte-deficient tumors improves mouse GBM survival.•Blocking neutrophil, but not monocyte, infiltration in HCC prolongs mouse survival.

SummaryMonocytes and monocyte-derived macrophages (MDM) from blood circulation infiltrate and promote glioblastoma growth. Here we discover that glioma cells induce the expression of potent pro-inflammatory cytokine IL-1β in MDM, which engages IL-1R1 in glioma cells, activates NF-κB pathway, and subsequently leads to the induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between the tumors and MDM creates an interdependence driving glioblastoma progression. Locally antagonizing IL-1β/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, reduced exhausted CD8+T cells, and thereby extends the survival of tumor-bearing mice. In contrast to IL-1β, IL-1a exhibits anti-tumor effects. Genetic deletion ofIl1ais associated with decreased recruitment of lymphoid cells and loss of interferon (IFN) signaling in various immune populations and subsets of malignant cells. IL-1β antagonism of IL-1β should be considered as an effective anti-glioblastoma therapy.Graphical Abstract