Abstract Tumour-associated macrophages (TAMs) are crucial components of the tumour microenvironment and play a significant role in tumour development and drug resistance by creating an immunosuppressive microenvironment. Macrophages are essential components of both the innate and adaptive immune systems and contribute to pathogen resistance and the regulation of organism homeostasis. Macrophage function and polarization are closely linked to altered metabolism. Generally, M1 macrophages rely primarily on aerobic glycolysis, whereas M2 macrophages depend on oxidative metabolism. Metabolic studies have revealed that the metabolic signature of TAMs and metabolites in the tumour microenvironment regulate the function and polarization of TAMs. However, the precise effects of metabolic reprogramming on tumours and TAMs remain incompletely understood. In this review, we discuss the impact of metabolic pathways on macrophage function and polarization as well as potential strategies for reprogramming macrophage metabolism in cancer treatment. 

Metabolism, metabolites, and macrophages in cancer

Electron paramagnetic resonance (EPR) spectroscopy is widely used to study free radicals or paramagnetic centers associated with biopolymers. With the advent of pulsed EPR methods, which allow accurate distance measurements between 20 and 80 , structures of biopolymers have increasingly been interrogated by this technique. Some of the advantages of EPR spectroscopy over other structural techniques are its sensitivity, that it is not restricted by molecular size, and that measurements can be performed under biological conditions. However, stable free radicals, such as nitroxide spin labels, must be incorporated into the biopolymers prior to EPR studies. In site-directed spin labeling (SDSL), spin labels are covalently attached to the biopolymers at a specific site of interest. For nucleic acids there have been two main strategies for SDSL. First, spin labels have been incorporated during automated oligonucleotide synthesis by employing spin-labeled phosphoramidite building blocks. This approach has the advantage that very sophisticated and structurally complex labels can be incorporated at specific sites. However, the synthetic challenges of spin-labeled phosphoramidites can be considerable. Furthermore, spin labels can be partially reduced upon exposure to the reagents used in the automated synthesis of oligonucleotides. The second SDSL approach is post-synthetic modification of the biopolymer. Here, a spin-labeling reagent is incubated with an oligonucleotide that contains a reactive functional group at a specific site. Post-synthetic labeling is in general less labor intensive than the phosphoramidite strategy, but drawbacks include incomplete labeling and side reactions of the spin label with inherent functional groups of the nucleic acids, such as the exocyclic amino groups of the nucleobases. Both strategies usually require purification of the spin-labeled material, which can be nontrivial. Here we report a new and straightforward SDSL protocol for nucleic acids that is based on noncovalent labeling. The new approach utilizes a nitroxide that is structurally related to the rigid spin label Ç. The spin label Ç is an analogue of cytidine (C), with a nitroxide-bearing isoindol moiety fused to cytosine by an oxazine linkage, and forms a stable Watson–Crick base pair with guanine (Figure 1). The rigidity of Ç enabled precise distance measurements by EPR, determination of the relative angular orientation between two spin labels, and has been used to study DNA dynamics and folding. 7] The strategy for noncovalent labeling was to disconnect the glycosidic bond of Ç to give an abasic site (F) and the free spin-labeled base (Figure 1). The spin label would bind in the abasic site through receptor–ligand interactions involving hydrogen bonding and p-stacking interactions. The synthesis of spin label started with regioselective alkylation of 5-bromouracil at N1 by a one-pot, two-step procedure using HMDS and benzyl bromide in the presence of a catalytic amount of iodine to obtain compound 2 (Scheme 1). Activation of 2 by conversion to the Osulfonylated derivative, followed by coupling with isoindol amino phenol derivative 4 yielded conjugate 5. Subsequent ring closure, facilitated by cesium fluoride, yielded phenoxazine derivative 6. Removal of the N1-protecting benzyl group by boron tribromide and oxidation of the amine to a nitroxide with mCPBA gave spin label . The EPR spectrum of in an aqueous solution containing ethylene glycol (30%) shows three narrow lines that broaden on reducing the temperature from 0 to 30 8C (Figure 2, left), due to slower tumbling of in solution. On mixing a DNA duplex containing an abasic site with , a slow-moving component appears in the EPR spectrum (shown by arrows, Figure 2 middle), indicating binding of the spin label to the abasic site. On further cooling, the extent of spin-label binding increased, and at 30 8C the narrow lines (the fastmotion component of the spectrum) had completely disappeared, consistent with the spin label being fully bound. For comparison, EPR spectra of a covalently Ç-labeled 14-mer were recorded under identical conditions (Figure 2, right). The mobility of the spin label that is covalently linked to the dsDNA is the same as that of the slow-moving component in the sample containing and the abasic DNA (Figure 2, Figure 1. a) Base-pairing scheme of spin labels Ç and with G. dR is 2’-deoxyribose. b) Structure of an abasic site in DNA.

Noncovalent and Site‐Directed Spin Labeling of Nucleic Acids

Preparation of acyclo nucleoside phosphonate analogues based on cross-metathesis

The 1-N-benzyl-5-iodo(or bromo)uracil undergoes Pd-catalyzed [Pd2(dba)3] direct arylation with benzene and other simple arenes in the presence of TBAF in DMF without the necessity of adding any ligands or additives to give 5-arylated uracil analogues. The TBAF-promoted coupling also occurs efficiently with electron rich heteroarenes at 100 °C (1 h) even with only small excess of heteroarenes. The protocol avoids usage of the arylboronic acid or stannane precursors for the synthesis of 5-(2-furyl, or 2-thienyl, or 2-pyrrolyl)uracil nucleosides, which are used as important RNA and DNA fluorescent probes. The fact that 1-N-benzyl-3-N-methyl-5-iodouracil did not undergo the TBAF-promoted couplings with arenes or heteroarenes suggests that the C4-alkoxide (enol form of uracil) facilitates coupling by participation in the intramolecular processes of hydrogen abstraction from arenes. TBAF-promoted arylation was extended into the other enolizable heterocyclic systems such as 3-bromo-2-pyridone. The π-excessive he...

Palladium-catalyzed direct arylation of 5-halouracils and 5-halouracil nucleosides with arenes and heteroarenes promoted by TBAF.

1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents.

Regioselective synthesis of 1-allyl- and 1-arylmethyl uracil and thymine derivatives

Tumor-associated macrophages (TAMs) exist in multiple phenotypes across the spectrum, defined by an M1 antitumorigenic phenotype and an M2 pro-tumorigenic phenotype on two ends of the spectrum. A largely immunosuppressive tumor-microenvironment aids the polarization of the infiltrating macrophages to a pro-tumorigenic M2 phenotype that promotes tumor progression and metastasis. Recent developments in macrophage immunotherapy have focused on strategies to re-educate TAMs from an M2 to M1 phenotype. Recent findings in the realm of immuno-metabolism have indicated that distinct metabolic signatures accompany macrophages based on their polarization states (M1-Glycolysis and M2-TCA cycle). These metabolites are important drivers of cellular signaling responsible for acquiring these polarization states, with evidence showing that metabolism is essential to facilitate the energy requirements of immune cells and regulate immune cell response. We hypothesized that TAMs could be reprogrammed metabolically by co-delivery of drugs using a supramolecular nanoparticle system that could effectively rewire macrophage metabolism by simultaneous inhibition of the TCA cycle and upregulation of the glycolytic metabolic pathway. TLR7/8 agonist and Fatty Acid Oxidation (FAO) inhibitor loaded metabolic supramolecular nanoparticles (MSNPs) were synthesized. In vitro assays showed macrophages treated with MSNPs were reprogrammed from an M2 phenotype to an M1 phenotype while significantly upregulating phagocytosis. When injected in 4T1 tumor-bearing mice, MSNPs treatment reduced tumor growth progression more than other treatments. Hence, the delivery of TLR7/8 agonist combined with an FAO inhibitor can enhance antitumor efficacy through metabolic reprogramming of tumor-associated macrophages.

Supramolecular nanotherapeutics enable metabolic reprogramming of tumor-associated macrophages to inhibit tumor growth.

2,4-Bis(trimethylsiloxy) pyrimidines 1 with allyl halides and arylmethyl halides in 1,2-dichloroethane in the presence of I2 regioselectively provide 1-allyl-/1-arylmethyl-uracil and thymine derivatives. The secondary aryl alkyl and diaryl methyl halides with 1 provide chiral 1-arylalkyl/1-(diarylmethyl) uracil/thymine derivatives. The procedure has been extended to the synthesis of fluorescent uracil/thymine derivatives.

Regioselective Synthesis of 1‐Allyl‐ and 1‐Arylmethyl Uracil and Thymine Derivatives.

Diagnosis of inflammatory diseases is characterized by identifying symptoms, biomarkers, and imaging. However, conventional techniques lack the sensitivities and specificities to detect disease early. Here, it is demonstrated that the detection of macrophage phenotypes, from inflammatory M1 to alternatively activated M2 macrophages, corresponding to the disease state can be used to predict the prognosis of various diseases. Activatable nanoreporters that can longitudinally detect the presence of the enzyme Arginase 1, a hallmark of M2 macrophages, and nitric oxide, a hallmark of M1 macrophages are engineered, in real-time. Specifically, an M2 nanoreporter enables the early imaging of the progression of breast cancer as predicted by selectively detecting M2 macrophages in tumors. The M1 nanoreporter enables real-time imaging of the subcutaneous inflammatory response that rises from a local lipopolysccharide (LPS) administration. Finally, the M1-M2 dual nanoreporter is evaluated in a muscle injury model, where an initial inflammatory response is monitored by imaging M1 macrophages at the site of inflammation, followed by a resolution phase monitored by the imaging of infiltrated M2 macrophages involved in matrix regeneration and wound healing. It is anticipated that this set of macrophage nanoreporters may be utilized for early diagnosis and longitudinal monitoring of inflammatory responses in various disease models.

Activatable Nanoreporters for Real-Time Tracking of Macrophage Phenotypic States Associated with Disease Progression.

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Regioselective synthesis of 1-allyl- and 1-arylmethyl uracil and thymine derivatives

Supramolecular nanotherapeutics enable metabolic reprogramming of tumor-associated macrophages to inhibit tumor growth.

Regioselective Synthesis of 1‐Allyl‐ and 1‐Arylmethyl Uracil and Thymine Derivatives.

Activatable Nanoreporters for Real-Time Tracking of Macrophage Phenotypic States Associated with Disease Progression.