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Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2[alpha] signaling. Identifying means to regulate HIF-2[alpha] thus has potential therapeutic benefit. Acetyl- CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2[alpha] and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2[alpha] levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2[alpha]. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF- 2[alpha] expression and stability. While HIF-2[alpha] protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHLindependent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2[alpha] and that overexpression of MUL1 decreased HIF-2[alpha] levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2[alpha] stability and ACSS2 inhibition as a strategy to complement HIF-2[alpha]-targeted therapies and deplete pathogenically stabilized HIF-2[alpha]., Introduction Clear cell renal cell carcinoma (ccRCC) is the most abundant subtype of kidney cancer, accounting for 75% of all cases (1). In ccRCC, a deregulated hypoxia transcriptional response is [...]

Immunometabolism is a burgeoning field of research that investigates how immune cells harness nutrients to drive their growth and functions. Myeloid cells play a pivotal role in tumor biology, yet their metabolic influence on tumor growth and antitumor immune responses remains inadequately understood. This Review explores the metabolic landscape of tumor-associated macrophages, including the immunoregulatory roles of glucose, fatty acids, glutamine, and arginine, alongside the tools used to perturb their metabolism to promote antitumor immunity. The confounding role of metabolic inhibitors on our interpretation of myeloid metabolic phenotypes will also be discussed. A binary metabolic schema is currently used to describe macrophage immunological phenotypes, characterizing inflammatory M1 phenotypes, as supported by glycolysis, and immunosuppressive M2 phenotypes, as supported by oxidative phosphorylation. However, this classification likely underestimates the variety of states in vivo. Understanding these nuances will be critical when developing interventional metabolic strategies. Future research should focus on refining drug specificity and targeted delivery methods to maximize therapeutic efficacy., Therapeutic potential of targeting macrophage metabolism in cancer Immunometabolism is a rapidly growing area of study that explores how immune cells employ various nutrients to support their growth and functionality. [...]

The synthesis of serine from glucose is a key metabolic pathway supporting cellular proliferation in healthy and malignant cells. Despite this, the role that this aspect of metabolism plays in germinal center biology and pathology is not known. Here, we performed a comprehensive characterization of the role of the serine synthesis pathway in germinal center B cells and lymphomas derived from these cells. We demonstrate that upregulation of a functional serine synthesis pathway is a metabolic hallmark of B cell activation and the germinal center reaction. Inhibition of phosphoglycerate dehydrogenase (PHGDH), the first and rate-limiting enzyme in this pathway, led to defective germinal formation and impaired high-affinity antibody production. In addition, overexpression of enzymes involved in serine synthesis was a characteristic of germinal center B cell-derived lymphomas, with high levels of expression being predictive of reduced overall survival in diffuse large B cell lymphoma. Inhibition of PHGDH induced apoptosis in lymphoma cells, reducing disease progression. These findings establish PHGDH as a critical player in humoral immunity and a clinically relevant target in lymphoma., Introduction B cells play a critical role in the humoral immune response that eliminates threats to the host by secreting highly specific antibodies. Activated B cells (ABCs) can either differentiate [...]

The relevance of molecular mechanisms governing mitochondrial proteostasis to the differentiation and function of hematopoietic and immune cells is largely elusive. Through dissection of the network of proteins related to HCLS1-associated protein X-1, we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB. As shown by stable isotope labeling by amino acids in cell culture (SILAC) proteomics, CLPB and HAX1 control the balance of mitochondrial protein synthesis and persistence crucial for proper mitochondrial function. Impaired mitochondrial protein dynamics are associated with decreased abundance of the serine-threonine kinase PRKD2 and HSP27 phosphorylated on serines 78 and 82. Cellular defects in [HAX1.sup.-/-] cells can be functionally reconstituted by HSP27. Thus, mitochondrial proteostasis emerges as a critical molecular and metabolic mechanism governing the differentiation and function of neutrophil granulocytes., Introduction Neutrophil granulocytes are critical mediators of innate immunity (1). In a highly controlled process of granulopoiesis, granulocyte-monocyte progenitors develop into mature neutrophils (2, 3). This developmental path is orchestrated [...]

The functional integrity of [CD8.sup.+] T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs [CD8.sup.+] T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the [CD8.sup.+] T cell metabolic state and antitumor functions. SENP7-deficient [CD8.sup.+] T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, [CD8.sup.+] T cell-derived ROS triggered cytosolic SENP7-mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell-intrinsic ROS restricted SENP7 cytosolic translocation and repressed [CD8.sup.+] T cell metabolic and functional activity in human colorectal cancer samples. Our findings reveal that SENP7, as an oxidative stress sensor, sustains [CD8.sup.+] T cell metabolic fitness and effector functions and unveil an oxidative stress-sensing machinery in tumor-infiltrating [CD8.sup.+] T cells., Introduction [CD8.sup.+] T cells mediate potent antitumor functions and play a critical role in immunotherapy-induced immune responses against cancer (1-3). Functionality and metabolic fitness are central determinants of [CD8.sup.+] T [...]

As cancers progress, they produce a local environment that acts to redirect, paralyze, exhaust, or otherwise evade Immune detection and destruction. The tumor microenvironment (TME) has long been characterized as a metabolic desert, depleted of essential nutrients such as glucose, oxygen, and amino acids, that starves infiltrating immune cells and renders them dysfunctional. While not incorrect, this perspective is only half the picture. The TME is not a metabolic vacuum, only consuming essential nutrients and never producing by-products. Rather, the by-products of depleted nutrients, 'toxic' metabolites in the TME such as lactic acid, kynurenine, ROS, and adenosine, play an important role in shaping immune cell function and cannot be overlooked in cancer immunotherapy. Moreover, while the metabolic landscape is distinct, it is not unique, as these toxic metabolites are encountered in non-tumor tissues, where they evolutionarily shape immune cells and their response. In this Review, we discuss how depletion of essential nutrients and production of toxic metabolites shape the immune response within the TME and how toxic metabolites can be targeted to improve current cancer immunotherapies., Introduction Cancer immunotherapy has revolutionized the treatment of cancer, unlocking the door to durable disease-free states in a subset of patients. Accompanying this major advancement is an improved understanding of [...]