Immunometabolism has emerged as a major mechanism central to adaptive and innate immune regulation. From early observations that inflammatory cytokines were induced in obese adipose tissue and that these cytokines contributed to metabolic disease, it was clear that metabolism and the immunological state are inextricably linked. With a second research wave arising from studies in cancer metabolism to also study the intrinsic metabolic pathways of immune cells themselves and how those pathways influence cell fate and function, immunometabolism is a rapidly maturing area of research. Several key themes and goals drive the field. There is abundant evidence that metabolic pathways are closely tied to cell signaling and differentiation which leads different subsets of immune cells to adopt unique metabolic programs specific to their state and environment. In this way, metabolic signaling drives cell fate. It is also apparent that microenvironment greatly influences cell metabolism.Immune cells adopt programs specific for the tissues where they infiltrate and reside.Ultimately, a central goal of the field is to apply immunometabolism findings to the discovery of novel therapeutic strategies in a wide range of diseases, including cancer, autoimmunity, and metabolic syndrome. This review summarizes these facets of immunometabolism and highlights opportunities for clinical translation. K E Y W O R D S autoimmunity, immune-mediated diseases, infectious diseases, metThis article introduces a series of reviews covering Immunometabolism: From Basic Mechanisms to Translation appearing in Volume 295 of Immunological Reviews.

Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that most patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers, but impacts on breast cancer (BC) remain unknown. In lean and obese mice, tumor progression and immune reprogramming were quantified in BC tumors treated with anti-programmed death-1 (PD-1) or control. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. BC primes systemic immunity to be highly responsive to obesity, leading to greater immunosuppression, which may explain greater anti-PD-1 efficacy. Anti-PD-1 significantly reinvigorates antitumor immunity despite persistent obesity. Laminin subunit beta-2 (Lamb2), downregulated by anti-PD-1, significantly predicts patient survival. Lastly, a microbial signature associated with anti-PD-1 efficacy is identified. Thus, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity.

Bile acids (BAs) are known facilitators of nutrient absorption but recent paradigm shifts now recognize BAs as signaling molecules regulating both innate and adaptive immunity. Bile acids are synthesized from cholesterol in the liver with subsequent microbial modification and fermentation adding complexity to pool composition. Bile acids act on several receptors such as Farnesoid X Receptor and the G proteincoupled BA receptor 1 (TGR5). Interestingly, BA receptors (BARs) are expressed on immune cells and activation either by BAs or BAR agonists modulates innate and adaptive immune cell populations skewing their polarization toward a more tolerogenic anti-inflammatory phenotype. Intriguingly, recent evidence also suggests that BAs promote anti-tumor immune response through activation and recruitment of tumoricidal immune cells such as natural killer T cells. These exciting findings have redefined BA signaling in health and disease wherein they may suppress inflammation on the one hand, yet promote anti-tumor immunity on the other hand. In this review, we provide our readers with the most recent understanding of the interaction of BAs with the host microbiome, their effect on innate and adaptive immunity in health and disease with a special focus on obesity, bariatric surgery-induced weight loss, and immune checkpoint blockade in cancer. K E Y W O R D S bariatric surgery, immunometabolism, microbiome, mitochondria, obesity, tumor microenvironment | 221 SIPE Et al.

The tumor microenvironment (TME) is a complex network of epithelial and stromal cells, wherein stromal components provide support to tumor cells during all stages of tumorigenesis. Among these stromal cell populations are myeloid cells, which are comprised mainly of tumor-associated macrophages (TAM), dendritic cells (DC), myeloid-derived suppressor cells (MDSC), and tumor-associated neutrophils (TAN). Myeloid cells play a major role in tumor growth through nurturing cancer stem cells by providing growth factors and metabolites, increasing angiogenesis, as well as promoting immune evasion through the creation of an immune-suppressive microenvironment. Immunosuppression in the TME is achieved by preventing critical anti-tumor immune responses by natural killer and T cells within the primary tumor and in metastatic niches. Therapeutic success in targeting myeloid cells in malignancies may prove to be an effective strategy to overcome chemotherapy and immunotherapy limitations. Current therapeutic approaches to target myeloid cells in various cancers include inhibition of their recruitment, alteration of function, or functional re-education to an antitumor phenotype to overcome immunosuppression. In this review, we describe strategies to target TAMs and MDSCs, consisting of single agent therapies, nanoparticle-targeted approaches and combination therapies including chemotherapy and immunotherapy. We also summarize recent molecular targets that are specific to myeloid cell populations in the TME, while providing a critical review of the limitations of current strategies aimed at targeting a single subtype of the myeloid cell compartment. The goal of this review is to provide the reader with an understanding of the critical role of myeloid cells in the TME and current therapeutic approaches including ongoing or recently completed clinical trials.

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