The PI3K/PTEN signaling pathway regulates development and function of innate cells. Genetic deletion of PTEN leads to hyper-activation of the PI3K pathway and its downstream signaling via Akt and mTOR resulting in the polarization of myeloid cells towards a less inflammatory phenotype. In models of acute infection and inflammation, myeloid PTEN-deficient mice (PTENfl/fl LysM) respond with less production of inflammatory and increased production of anti-inflammatory factors. In contrast, in a model of bleomycin induced lung fibrosis, conditional PTEN-KO mice exhibit enhanced fibrosis and inflammation. In models for autoimmunity, T-cell responses are attenuated and myeloid PTEN-deficient mice show protection from these diseases. We hypothesized that the observed anti-inflammatory phenotype in PTENfl/fl LysM cre mice would reduce tumor immune surveillance, since an active immune system is indispensable for prohibiting tumor development. We addressed this issue using an endogenously grown and an implanted tumor model, the colitis associated colon cancer and the B16-melanoma model. Applying the former model, we observed an increase in tumor burden and mortality in myeloid PTEN-deficient mice. In addition, these animals exhibited elevated numbers of CD8[alpha]+ dendritic cells in their spleens that are capable of cross-presenting antigen. This finding was further substantiated by the observation that activation of the transcriptional program necessary to develop CD8[alpha]+ dendritic cells was more pronounced in PTENfl/fl LysM cre mice. These antigen-presenting cells expressed the immune checkpoint molecules PD-L1 and PD-L2 thereby blocking CD8+ T-cell proliferation ex vivo and in vivo significantly. In the B16-melanoma model myeloid PTEN-deficient mice also exhibited an increase in tumor size. T-cells showed reduced capabilities to lyse tumor cells. Additionally, their T-helper cells showed signs of a regulatory phenotype. Continuing the work on adaptive-immune regulating dendritic cells and the PI3K signaling therein, we used a more DC-specific PTEN knock-out model, the PTENfl/fl CD11c cre mouse. These mice showed an even more severe phenotype than the myeloid PTEN-KO animals in the colon cancer model, with even higher mortality that started already during the inflammatory phase of the model. Additionally, even in acute and chronic colitis models we observed mortality in DC-specific PTEN-KO animals when wildtype controls survived. We found reduced numbers of T-cells in the secondary lymphoid organs of these mice, whereas dendritic cells were increased in numbers and showed an increased expression of co-stimulatory and inhibitory surface molecules. Conversely, T-cells from conditional KOs produced more IFN[gamma] upon re-stimulation. In addition, PTENfl/fl CD11c mice showed an increased bacterial burden during colitis and a concomitant enlargement of the spleen, suggesting that T-cell responses might not be initiated efficiently or are even actively suppressed. In summary, the PI3K/PTEN signaling pathway affects myeloid cell development and polarization. During infection and inflammation, myeloid PTEN-deficient mice show a phenotypic shift in innate cells towards reduced inflammation. This reduced inflammatory response is detrimental during tumor development as immune surveillance is impaired, allowing for an unhindered tumor growth. Our data suggest that blocking PI3K signaling might have additional beneficial effects in cancer treatment by activating tumor immune surveillance via the innate immune system.