Targeting PPAR ligands as possible approaches for metabolic reprogramming of T cells in cancer immunotherapy.

Despite the prominent progress in understanding cancer immunosurveillance mechanisms, there are some types of problems which have been identified to hinder effective and successful immunotherapy of cancers. Such problems have been ascribed to the tumor abilities in the creation of a tolerant milieu that can impair immune responses against cancer cells. In the present study, we represent possible approaches for metabolic reprogramming of T cells in cancer immunotherapy to overcome tumor metabolic impositions on immune responses against cancer cells. Metabolic suppression of effector immune cells in tumor milieu is one of the important strategies recruited by tumor cells to escape from immunogenic cell death. We have investigated the metabolic reprogramming of T cells as a method and a possible new target for cancer immunotherapy. Synergic effects of PPAR ligands in immunotherapy of cancers on the metabolic reprogramming of T cells have been noticed by several studies as a new target of cancer immunotherapy. The current wealth of data like this promises a future scenario which the consideration of metabolic restriction in the tumor microenvironment and administration of therapeutic agents such as PPAR ligands to overcome metabolic restrictions on T cells (refreshing their functionality) may be effective and enhance the accountability and efficacy of cancer immunotherapy.

Bahrambeigi S ，Molaparast M ，Sohrabi F ，Seifi L ，Faraji A ，Fani S ，Shafiei-Irannejad V ... -  《-》

Immune-mediated anti-tumor effects of metformin; targeting metabolic reprogramming of T cells as a new possible mechanism for anti-cancer effects of metformin.

Immunotherapy-based cancer treatment has revolutionized the era of cancer patients recuperation and it has brought a strong hope to treatment of some types of cancers. Metformin, a widely used antidiabetic drug, which has intensely been studied for its anticancer effects, is believed to have positive influences on immune responses against tumor cells. Metformin can affect metabolic pathways within cells mainly through activation of AMPK. Metabolic restriction of tumor microenvironment on effector immune cells is one of the important strategies favoring tumor cells to escape from immunogenic cell death. The metabolism of T cells has an axial role in shaping and supporting immune responses and may have an important role in anticancer immunity, suggesting that the functionality and durability of tumor-specific T cells need sufficient energy and nutrients. Energy biogenesis of tumor-specific cytotoxic T cells has become an interesting field of study and it is suggested that activation and maintenance of effector T cell responses in tumor microenvironment may occur by metabolic reprogramming of T cells. AMPK has been noticed as the main intracellular energy sensor and mitochondrial biogenesis key regulator which can control and regulate metabolic reprogramming in immune cells and increase antitumor immunity. Metabolic reprogramming of T cells to overcome metabolic restriction in tumor microenvironment, maiming effector T cell responses against tumor cells, has been noticed by several studies. Here we represent metformin, an AMPK activator, as a new candidate drug for metabolic reprogramming of tumor-specific T cells to increase the efficacy and accountability of cancer immunotherapy.

Bahrambeigi S ，Shafiei-Irannejad V 《-》

Harnessing Metabolic Reprogramming to Improve Cancer Immunotherapy.

Yan L ，Tan Y ，Chen G ，Fan J ，Zhang J ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Major fundamental factors hindering immune system in defense against tumor cells: The link between insufficiency of innate immune responses, metabolism, and neurotransmitters with effector immune cells disability.

Despite the major progresses in comprehending the mechanisms of tumor immunosurveillance and the role of innate and adaptive immune systems in recent years, there are still a number of obstacles hindering successful and effective immunotherapy of cancer. Such obstacles have been mainly attributed to the ability of tumors in creating a tolerant microenvironment and exploiting a plethora of immunosuppressive factors that counter effective immune responses against tumor cells. Here we represent a new insight into probable links between immune system disability with metabolism and chronic psychological stress which is beyond the other strategies recruited by tumors to thwart tumor immunosurveillance. In addition, we underscore the prominent role of improper innate immune responses as one of the underlying causes of either pro-tumorigenic capability or tumor immunosurveillance failure. However the insufficiency of stimulatory factors in immune responses is a major fact leading to tumor survival, metabolic suppression of immune cells in tumor microenvironment, as well as the negative influences of chronic stress and depression in cancer patients are important parameters amplifying disability of immune responses which have mostly been underestimated in cancer immunotherapy. Stress-related catecholamines are suggested as immunosuppressive factors. In addition, tumor cells have distinct metabolic pathways and secrete various metabolites in the tumor microenvironment which may inhibit T cells activity. We believe that simultaneous control of metabolic and psychological negative influences on the tumor immunosurveillance, along with addressing the weak aspects of innate and adaptive immune responses in cancer immunotherapy may result in more successful treatment of tumors.

Bahrambeigi S ，Sanajou D ，Shafiei-Irannejad V 《-》

Immunometabolism: A new target for improving cancer immunotherapy.

Fundamental metabolic pathways are essential for mammalian cells to provide energy, precursors for biosynthesis of macromolecules, and reducing power for redox regulation. While dysregulated metabolism (e.g., aerobic glycolysis also known as the Warburg effect) has long been recognized as a hallmark of cancer, recent discoveries of metabolic reprogramming in immune cells during their activation and differentiation have led to an emerging concept of "immunometabolism." Considering the recent success of cancer immunotherapy in the treatment of several cancer types, increasing research efforts are being made to elucidate alterations in metabolic profiles of cancer and immune cells during their interplays in the setting of cancer progression and immunotherapy. In this review, we summarize recent advances in studies of metabolic reprogramming in cancer as well as differentiation and functionality of various immune cells. In particular, we will elaborate how distinct metabolic pathways in the tumor microenvironment cause functional impairment of immune cells and contribute to immune evasion by cancer. Lastly, we highlight the potential of metabolically reprogramming the tumor microenvironment to promote effective and long-lasting antitumor immunity for improved immunotherapeutic outcomes.

Guo C ，Chen S ，Liu W ，Ma Y ，Li J ，Fisher PB ，Fang X ，Wang XY ... -  《-》