PTEN hamartoma tumor syndrome (PHTS) is caused by inactivating germline PTEN mutations with subsequent activation of Akt-mTOR signaling, leading to an increased risk of developing thyroid carcinoma (TC). Activation of Akt-mTOR signaling is essential for innate immune cell activation and reprogramming of TC-induced macrophages. Here, we aim to assess the effect of PTEN mutations on innate immune cell function in PHTS patients, especially in the context of TC, using a unique ex vivo model. Monocyte-derived cytokine responses were assessed in 29 PHTS patients and 29 controls. To assess the functional profile of TC-induced-macrophages, a co-culture model with two TC cell lines was performed. Rapamycin, a lactate transport blocker and metformin were used as modulators of the Akt-mTOR pathway and cell metabolism. Monocytes from PHTS patients showed increased production of IL-6, TNF-α, IL-8 and MCP-1, and higher lactate production. After co-culture with TC cell lines, TC-induced macrophages showed significantly increased production of cytokines in both patients and controls, especially after co-culture with a PTEN-deficient TC cell line; these effects were abolished after use of rapamycin or a lactate transport blocker. Metformin blocked the production of anti-inflammatory cytokines. In conclusion, innate immune cells from PHTS patients have increased lactate production and a more proinflammatory phenotype, especially after co-culture with PTEN-deficient TC. Metformin promotes a proinflammatory phenotype by blocking anti-inflammatory cytokine response, whereas rapamycin reduces production of proinflammatory cytokines. This indicates that PHTS patients may benefit from treatment with mTOR blocking agents to limit the inflammatory response in the tumor microenvironment.