LAUSR

Simple Summary Metabolic reprogramming is one of tumor and immune cells’ most significant metabolic alterations. Moreover, metabolic-related signaling pathways, such as phosphoinositide 3-kinases (PI3Ks), the mammalian target of rapamycin (mTOR), can induce growth, proliferation, and angiogenesis of tumor cells. Therefore, inhibiting these metabolic pathways can be considered a potential therapeutic strategy in human malignancies. On the other hand, according to previous studies, pharmacological inhibiting of metabolic pathways using dual-pathway inhibitors can considerably inhibit tumor growth and progression, more than suppressing each pathway separately. This review aims to summarize the latest metabolic interventions by dual pathway inhibitors and discuss the achievements and limitations of this therapeutic tactic. Abstract The metabolism of tumors and immune cells in the tumor microenvironment (TME) can affect the fate of cancer and immune responses. Metabolic reprogramming can occur following the activation of metabolic-related signaling pathways, such as phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR). Moreover, various tumor-derived immunosuppressive metabolites following metabolic reprogramming also affect antitumor immune responses. Evidence shows that intervention in the metabolic pathways of tumors or immune cells can be an attractive and novel treatment option for cancer. For instance, administrating inhibitors of various signaling pathways, such as phosphoinositide 3-kinases (PI3Ks), can improve T cell-mediated antitumor immune responses. However, dual pathway inhibitors can significantly suppress tumor growth more than they inhibit each pathway separately. This review discusses the latest metabolic interventions by dual pathway inhibitors as well as the advantages and disadvantages of this therapeutic approach.