Tumor microenvironment is infiltrated by a large number of macrophages which correlates with immune-checkpoint-therapy resistance in cancer. Macrophage infiltration is mediated by chemokine receptors such as CCR2 and CCR5 that are implicated in the tumor progression. However, the drug development targeting these receptors has been stymied, due to the complexity and the redundancy of chemokines/chemokine receptors network. We previously identified a novel protein FROUNT, an intracellular regulator of chemokine signals. FROUNT binds to CCR2 and CCR5, promoting the PI3K-mediated chemotactic signals (Nat. Immunol. 2005, J. Immunol. 2009, Biochem. J. 2014 and FEBS J. 2014). To assess the role of FROUNT in the tumor progression, we have generated FROUNT-deficient mice. FROUNT-deficiency exhibited impaired tumor growth and metastasis, accompanied by a decreased macrophage accumulation in the tumor sites. We have screened a compound library and have identified FROUNT inhibitors that block the interaction of FROUNT-chemokine receptors, interrupt macrophage infiltration and impair tumor progression. Furthermore, retrospective analysis of patients with lung adenocarcinoma revealed that when patients were divided into FROUNT-high, and -low groups based on the relative FROUNT mRNA median values for their lung specimens, recurrence and poor survival rates were significantly higher in the FROUNT-high group, suggesting that FROUNT expression is a novel risk factor for poor prognosis. Thus, our results suggest a new approach for cancer therapy, which controls PI3K-mediated macrophage infiltration by targeting FROUNT.