Lung cancer is one of the most lethal of solid tumors. The overall survival rate for patients with lung cancer remains low, at 21%. As 236,740 new cases of lung cancer and 130,180 deaths are expected in 2022, there remains a pressing need to advance research into new therapeutic approaches for the treatment of lung cancer. Solid tumors, such as lung tumors, are laden with abundant, tumor-promoting macrophages, monocytes and granulocytes. These innate immune cells promote tumor progression through profound inhibition of T cell recruitment and activation and through stimulation of tumor angiogenesis, stemness, drug resistance and metastasis. Strategies that reduce the accumulation of myeloid cells or alter their functional properties significantly slow or eliminate tumor progression in animal models of cancer and synergize with other therapeutic approaches to improve cancer outcomes. We previously discovered that a myeloid cell specific isoform of phosphatidylinositol-4,5-bisphosphate 3-kinase, PI3Kgamma (PI3Kg), controls both myeloid cell accumulation and immune suppressive polarization in tumors. Genetic or pharmacological inactivation of PI3Kg, but not other PI3K isoforms, reduces myeloid cell accumulation in tumors and alters the transcriptional profile of immune suppressive, pro-angiogenic tumor associated macrophages (TAMs) toward a pro-inflammatory, anti- tumor phenotype. We have found that PI3Kg inhibition synergizes with chemotherapy and with checkpoint inhibitors to activate memory T cells and reduce tumor growth in models of lung cancer, breast cancer, melanoma, head and neck cancer and glioblastoma. Based on our findings, the PI3Kg inhibitor, IPI-549 (eganelisib), was developed as an immune oncology therapeutic. We identified signatures of re-activated adaptive immune responses in tumor tissues from lung cancer patients who participated in IPI-549 Phase 1 clinical trials, indicating that PI3Kg blockade can re-awaken anti-tumor immunity in human tumors and thus may provide therapeutic benefit to lung cancer patients. However, we also identified pathways of resistance to therapy, indicating that further dissection of the roles that PI3Kg and its inhibitors play in lung tumors is warranted. The exact biochemical and cellular mechanisms by which PI3Kg inhibits anti-tumor immunity in murine and human lung cancer remain unclear. Deciphering these mechanisms will provide new therapeutic insights into the mechanisms of tumor immune suppression. Therefore, we propose studies to determine which molecular and cellular mechanisms are direct and indirect targets of PI3Kg mediated immune suppression, to identify and treat pathways of resistance to PI3Kg inhibitor therapy and to evaluate the impact of PI3Kg inhibition on immune responses in mouse and human models of NSCLC. The specific aims to accomplish these goals are: 1) To delineate molecular mechanisms by which PI3Kg regulates macrophage transcription; 2) To determine mechanisms by which PI3Kg co...