Survival benefit of adjuvant chemotherapy after resection of Stage I lung adenocarcinoma containing micropapillary components.

BACKGROUND: The usefulness of postoperative adjuvant chemotherapy (ACT) for patients with stage I lung adenocarcinoma with micropapillary (MIP) components remains unclear. We analyzed whether postoperative ACT could reduce recurrence in patients with stage I lung adenocarcinoma with MIP components, thereby improving their overall survival (OS) and disease-free survival (DFS). METHODS: Data for patients with pathologically confirmed stage I lung adenocarcinoma with MIP components from January 2012 to December 2018 were retrospectively analyzed. OS and DFS were analyzed in groups and subgroups. RESULTS: Overall, 259 patients were enrolled. Patients who received ACT in stage IA showed significantly better survival than did those with no-adjuvant chemotherapy (NACT); (5-year OS 89.4% vs. 73.6%, p < 0.001; 5-year DFS 87.2% vs. 66.0%, p = 0.008). A difference was also observed for in-stage IB patients (5-year OS 82.0% vs. 51.8%, p = 0.001; 5-year DFS 76.0% vs. 41.11 %, p = 0.004). In subgroup analysis based on the proportion of MIP components, patients with 1%-5% MIP components had a significantly better prognosis in the ACT group than in the NACT group (5-year OS 82.4% vs. 66.0%, p = 0.005; 5-year DFS 76.5% vs. 49.1%, p = 0.032). A similar difference was observed for patients with MIP ≥5% (5-year OS 80.7% vs. 47.8%, p = 0.009; 5-year DFS 73.11% vs. 43.5%, p = 0.007). CONCLUSION: Among patients with stage I lung adenocarcinoma with MIP components, those who received ACT showed significant survival benefits compared to those without ACT. Patients with lung adenocarcinoma with MIP components could benefit from ACT when the MIP was ≥1%.

Synthesis and performance study of PAM-g-PAA/PHEA and its application in purifying tellurium aerosol.

In this study, grafted polymers (PAM-g-PAA/PHEA) with different grafting rates are prepared by solution method grafting polymer with polyacrylamide as the main chain, acrylic acid (AA) and 2-hydroxyethyl acrylate (HEA) as the modified monomers. Evidence of graft polymerization of AA and HEA on polyacrylamide side chains is obtained by FT-IR and 1HNMR. Scanning electron microscopy and thermogravimetric characterization further confirm the synthesis of grafted polymers. The properties of the grafting polymer are evaluated using grafting rate, viscosity, and surface tension measurements. The performance of polymer aqueous solution as an aerosol fixative for capturing and removing tellurium aerosol as a simulated polonium aerosol is examined. According to the results, grafting two monomers, acrylic acid, and 2-hydroxyethyl acrylate, effectively improve the cross-sectional structure of the polymer, increase the thermal stability of the polymer, and reduced the surface tension of the aqueous polymer solution to 42.47 mN/m. In addition, aerosol settling and fixation experiments showed that PAM-g-PAA/PHEA had a trapping and scavenging effect on tellurium aerosols with an immobilization rate of 94.86%, which revealed the immobilization mechanism of the immobilizer with tellurium aerosols.

Optimizing the dielectric constant of the shell layer in core-shell structures for enhanced energy density of polymer nanocomposites.

Improved dielectric constant and breakdown strength facilitates excellent energy storage density of polymer dielectrics, which is positive to miniaturize dielectric capacitors in electronic and electrical systems. Although coating polar substances on nanoparticles enhances the dielectric constants of polymer nanocomposites, it usually causes local electric field concentration, leading to poor breakdown strength. Here, fluoropolymers with tailorable fluorine content (PF0, PF30 and PF60) are coated on BaTiO3 (BT) nanoparticles to construct typical core-shell structures that are further blended with poly(vinylidenefluoride-co-hexafluoropropylene) (P(VDF-HFP)) to obtain BT@PF/P(VDF-HFP) nanocomposites. Uniform dispersion of nanoparticles and excellent compatibility of interfaces are observed for the samples. In addition, the dielectric constant gradually increases from 8.03 to 8.26 to 9.12 for the nanocomposites filled with 3 wt% BT@PF0, BT@PF30 and BT@PF60, respectively. However, 3 wt% BT@PF30/P(VDF-HFP) has the highest breakdown strength (455 kV mm-1) among the nanocomposites, which is as good as neat P(VDF-HFP). More importantly, BT@PF30 rather than BT@PF60 possesses the maximum discharged energy density (11.56 J cm-3 at 485 kV mm-1), which is about 1.65 times that of neat P(VDF-HFP). This work proposes a facile experimental route to optimize the dielectric constants of the shell layer to couple the dielectric constants between the nanoparticles, shell layer and polymer matrix, which contributes to alleviating the local electric field concentration for excellent breakdown strength and electrical energy storage of polymer nanocomposites.

Cadmium (Cd) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) co-exposure induces acute kidney injury through oxidative stress and RIPK3-dependent necroptosis.

Environmental pollution is complex, and co-exposure can accurately reflect the true environmental conditions that are important for assessment of human health. Cadmium (Cd) is a widespread toxicant that can cause acute kidney injury (AKI), while its combined effect with 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is not fully understood. Thus, we used an in vivo model where C57BL/6J mice were treated with low dietary intake of Cd (5 mg/kg/day) and/or BDE-47 (1 mg/kg/day) for 28 days to examine AKI, and in vitro experiments to investigate the possible mechanism. Results showed that Cd or BDE-47 caused pathological kidney damage, accompanied by elevated urea nitrogen (BUN) and urinary creatinine, as well as increased interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), and reduced IL-10 in kidney tissues. In vitro Cd or BDE-47 exposure decreased cell viability and induced cell swelling and blebbing of human embryonic kidney 293 (HEK-293) and renal tubular epithelial cell lines (HKCs), and changes in co-exposure was larger than that in Cd and BDE-47 treatment. Oxidative stress indicators of the reactive oxygen species (ROS) and malondialdehyde (MDA) were elevated, while the antioxidant superoxide dismutase (SOD) was decreased. Necrosis occurred with increased lactate dehydrogenase (LDH) release and propidium iodide (PI) staining, which was attenuated by the ROS scavenger N-acetyl-L-cysteine (NAC). Furthermore, necroptotic genes of receptor-interacting protein kinase-3 (RIPK3), classical mixed lineage kinase domain-like protein-dependent (MLKL), IL-1ß and TNF-α were up-regulated, whereas RIPK1 was down-regulated, which was attenuated by the RIPK3 inhibitor GSK872. These findings demonstrate that Cd or BDE-47 alone produces kidney toxicities, and co-exposure poses an additive effect, resulting in AKI via inducing oxidative stress and regulating RIPK3-dependent necroptosis, which offers a further mechanistic understanding for kidney damage, and the combined effect of environmental pollutants should be noticed.

Phosphorylation and Stabilization of PD-L1 by CK2 Suppresses Dendritic Cell Function.

Targeting immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has transformed cancer treatment, with durable clinical responses across a wide range of tumor types. However, a high percentage of patients fail to respond to anti-PD-1/PD-L1 treatment. A greater understanding of PD-L1 regulation is critical to improving the clinical response rate of PD-1/PD-L1 blockade. Here, we demonstrate that PD-L1 is phosphorylated and stabilized by casein kinase 2 (CK2) in cancer and dendritic cells (DC). Phosphorylation of PD-L1 at Thr285 and Thr290 by CK2 disrupted PD-L1 binding with speckle-type POZ protein, an adaptor protein of the cullin 3 (CUL3) ubiquitin E3 ligase complex, protecting PD-L1 from CUL3-mediated proteasomal degradation. Inhibition of CK2 decreased PD-L1 protein levels by promoting its degradation and resulted in the release of CD80 from DC to reactivate T-cell function. In a syngeneic mouse model, combined treatment with a CK2 inhibitor and an antibody against T-cell immunoglobulin mucin-3 (Tim-3) suppressed tumor growth and prolonged survival. These findings uncover a mechanism by which PD-L1 is regulated and suggest a potential antitumor treatment option to activate DC function by blocking the CK2-PD-L1 pathway and inhibiting Tim-3. SIGNIFICANCE: This work identifies a role for CK2 in immunosuppression by phosphorylation and stabilization of PD-L1, identifying CK2 inhibition as an immunotherapeutic approach for treating cancer.

Migration behavior and leaching ability of radioactive uranium during incineration of uranium-containing strippable coating wastes.

It is currently thought that the incineration approach is an effective method to minimize the volume of radioactive wastes. In this paper, we used an incinerator to burn uranium-containing strippable coating waste. The migration behavior of radioactive uranium during the incineration process were investigated based on hierarchical sampling and mass spectrometry. Results shows that the radioactive uranium is more easily to adhere to the particles with smaller size. The leaching abilities of radioactive uranium in the bottom ash and the fly ash were analyzed. The leaching rate of the uranium from the fly ash and bottom ash were 1% and 6%, respectively, indicating that most of the radioactive uranium was fixed in the ash and the same storage/disposal methods can be used for both the fly ash and bottom ash. According to x-ray spectrometry and SEM-EDS, mineral compositions of the original uranium ore and the bottom ash were mostly the same. Calcium plays an important role in uranium fixation during incineration. The potential mechanism of the uranium special transformation during uranium-containing strippable coating waste combustion was revealed. Our research results can provide technical support for nuclear emergency waste treatment and disposal.

A ratiometric fluorescent nanoprobe for signal amplification monitoring of intracellular telomerase activity.

Telomerase is considered a valuable diagnostic and prognostic cancer biomarker. Accurate and reliable detection of telomerase activity is of great value in clinical diagnosis, screening of inhibitors, and therapeutics. Here, we developed a novel amplified fluorescence resonance energy transfer (FRET) nanoprobe for highly sensitive and reliable monitoring of intracellular telomerase activity. The nanoprobe (QDSA@DNA) was composed of a streptavidin-modified quantum dot (QDSA) which was functionalized with a telomerase primer sequence (TP) and Cy5-tagged signal switching sequence (SS) through biotin-streptavidin interaction. When the nanoprobe was assembled, the Cy5 was in close proximity to the QDSA, resulting in high FRET efficiency from the QDSA to Cy5. In the presence of telomerase, the TP could be extended to produce telomeric repeat units, which was complementary to the loop of SS. Thus, the SS could hybridize with elongated sequences to form a rigid double-stranded structure, which forced the Cy5 away from the surface of the QDSA, causing low FRET efficiency. Furthermore, due to the production of multiple repeat units by telomerase, multiple hairpin structures could be opened, yielding significant fluorescence ratio (FQDsa/FCy5) enhancement for sensing of telomerase activity. In this way, the combination of a FRET and target-assisted strategy in a nanoprobe improved the detection accuracy and amplified the detection signal, respectively. The QDSA@DNA nanoprobe also showed high selectivity, excellent nuclease stability, and good biocompatibility. More importantly, this nanoprobe was found to be an excellent platform for efficient monitoring of intracellular telomerase activity, providing a potential platform in tumor diagnosis and screening of telomerase-related inhibitors.

High loading BaTiO3 nanoparticles chemically bonded with fluorinated silicone rubber for largely enhanced dielectric properties of polymer nanocomposites.

Integrating high-loading dielectric nanoparticles into polar polymer matrices potentially can profit the intrinsic polarization of each phase and allow for greatly enhanced dielectric properties in polymer nanocomposites. It is however challenging to achieve desirable highly filled polar polymer composites because of the lack of efficient approaches to disperse nanoparticles and maintain interfacial compatibility. Here, we report a versatile route to fabricate highly filled barium titanate/fluorinated silicone rubber (BT/FSR) nanocomposites by "thiol-ene click" and isostatic pressing techniques. The loaded BT nanoparticles (from 82 wt% to 90 wt%) are chemically bonded with FSR in the nanocomposites. The existence of the polar group (-CH2CF3) of the polymer matrix does not affect the uniform dispersion of the nanoparticles or the good interfacial compatibility. The 90 wt% BT/FSR nanocomposite shows the highest dielectric constant of 57.8 at 103 Hz, while the loss tangent can be kept below 0.03. Besides, BT/FSR nanocomposites display higher breakdown strength than BT/SR nanocomposites. This work offers a facile strategy towards superior dielectric properties of polymer nanocomposites.

Megakaryocytes Mediate Hyperglycemia-Induced Tumor Metastasis.

High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKCα pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a platelet-adoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKCα pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. SIGNIFICANCE: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75.

PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through the inhibition of TM4 (UBAC2) degradation.

BACKGROUND: The TM4 (UBAC2) protein, which contains 4 transmembrane domains and one ubiquitin binding domain, is mainly expressed in cell and nuclear membranes. The current research aimed to explore the role of TM4 in metabolic inflammation and to examine whether the ubiquitin-proteasome inhibitor PS-341 could regulate the function of TM4. METHODS: The metabolic phenotypes of TM4 knockout (KO) mice were studied. We next explored the association between the polymorphisms of TM4 and obesity in a Chinese Han population. TM4 expression in the visceral fat of obese patients who underwent laparoscopic cholecystectomy was also analysed. Finally, the effect of PS-341 on the degradation and function of the TM4 protein was investigated in vivo and in vitro. RESULTS: TM4 KO mice developed obesity, hepatosteatosis, hypertension, and glucose intolerance under a high-fat diet. TM4 counterregulated Nur77, IKKß, and NF-kB both in vivo and in vitro. The TM4 SNP rs147851454 is significantly associated with obesity after adjusting for age and sex (OR 1.606, 95% CI 1.065-2.422 P = 0.023) in 3394 non-diabetic and 1862 type 2 diabetic adults of Han Chinese. TM4 was significantly downregulated in the visceral fat of obese patients. PS-341 induced TM4 expression through inhibition of TM4 degradation in vitro. In db/db mice, PS-341 administration led to downregulation of Nur77/IKKß/NF-κB expression in visceral fat and liver, and alleviation of hyperglycaemia, hypertension, and glucose intolerance. The hyperinsulinaemic-euglycaemic clamp demonstrated that PS-341 improved the glucose infusion rate and alleviated insulin resistance in db/db mice. CONCLUSIONS: PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through inhibition of TM4 degradation.

Self-Assembly of a Purely Covalent Cage with Homochirality by Imine Formation in Water.

Self-assembly of host molecules in aqueous media via metal-ligand coordination is well developed. However, the preparation of purely covalent counterparts in water has remained a formidable task. An anionic tetrahedron cage was successfully self-assembled in a [4+4] manner by condensing a trisamine and a trisformyl in water. Even although each individual imine bond is rather labile and apt to hydrolyze in water, the tetrahedron is remarkably stable or inert due to multivalence. The tetrahedral cages, as well as its neutral counterparts dissolved in organic solvent, have homochirality, namely that their four propeller-shaped trisformyl residues adopt the same rotational conformation. The cage is able to take advantage of hydrophobic effect to accommodate a variety of guest molecules in water. When a chiral guest was recognized, the formation of one enantiomer of the cage became more favored relative to the other. As a consequence, the cage could be produced in an enantioselective manner. The tetrahedron is able to maintain its chirality after removal of the chiral guest-probably on account of the cooperative occurrence of intramolecular forces that restrict the intramolecular flipping of phenyl units in the cage framework.

Direct detection of Pb2+ and Cd2+ in juice and beverage samples using PDMS modified nanochannels electrochemical sensors.

Direct electrochemical detection in real food samples remains challenging due to the fouling and interference by abundant interference components. Herein, we report an electrochemical sensing platform based on binary assembly of silica nanochannels and polydimethylsiloxane that is able to detect Pb2+ and Cd2+ in real food samples without complex pretreatments. Using differential pulse anodic stripping voltammetry, the electrochemical detection consists of electro-deposition of metal species and subsequent anodic stripping in the modified silica-nanochannels. Under the optimized conditions, the linear ranges were obtained from 4 to 1500 µg L-1 for Pb2+ and 30 to 900 µg L-1 for Cd2+. The relative standard deviations were 2.9% and 3.6% for Pb2+ and Cd2+ of 300 µg L-1. Without tedious pretreatments, the quantitative detection of Pb2+ and Cd2+ in real juice and beverage samples was successfully performed, revealing that the developed sensor possesses excellent anti-interference and practicability properties for unprocessed food.

Interference-free Detection of Caffeine in Complex Matrices Using a Nanochannel Electrode Modified with Binary Hydrophilic-Hydrophobic PDMS.

In the present study, a novel electrochemical sensor for the direct detection of caffeine in the crude sample has been prepared by plasma-triggered polydimethylsiloxane (PDMS) deposition on the indium tin oxide electrodes supported with silica nanochannels. The deposited PDMS contains both the original hydrophobic and oxidized hydrophilic PDMS oligomers. Nanochannels modified with these two kinds of PDMS with opposite wettability only allow the passage of small amphiphilic molecules such as caffeine, while other molecules including hydrophilic, hydrophobic, and large ones were all rejected. With the excellent shielding properties, the modified nanochannel electrode exhibits excellent anti-interference and antifouling capability, which could be directly used for the detection of caffeine in real crude food such as tea, milk, coffee, and coke without sample pretreatments. Moreover, the modified electrode has good repeatability and stability. In contrast, severe interference was observed when conventional electrodes were used directly in these unprocessed samples. The linear ranges of caffeine were determined to be between 50 nmol/L and 700 µmol/L, with a limit of detection of 20 nmol/L. The developed sensor provides a very simple, rapid, and cost-effective way for the interference-free and fouling-free analysis of specific amphiphilic compounds and can be extended to a wide range of applications.

Twice-FFT demodulation for signal distortion in optical fiber FP acoustic sensor.

A Twice-FFT demodulation method for signal distortion state is proposed and experimentally demonstrated in an optical fiber Fabry-Perot (FP) acoustic sensor. Here the fiber FP acoustic sensor element is build with fiber end face and combination of diaphragms which is composed of a small round aluminum foil and a polymer PET film. The hypotenuse intensity demodulation method is applied to acquire the acoustic signal in time domain assisted with a Photodetector (PD) and an oscilloscope. The first Fast Fourier transform (FFT) processing results show harmonic distortion on the frequency domain spectrum. To demodulate the acoustic frequency and amplitude information, twice-FFT processing is preformed. Experimental results reveal an accuracy up to 95.6% of acoustic signal in the frequency range 2-100 Hz. Our scheme provides a new option for signal demodulation of optical fiber acoustic sensors (OFAS).

Mutagenicity of 7-ketocholesterol in CHO cells: The role of lipid peroxidation.

As an important cholesterol oxide, 7-ketocholesterol plays a deleterious role in the occurrence of cancer. Although the fact had been proved that 7-ketocholesterol could induce several biological phenomena, including apoptosis, DNA damage, et al., this issue whether 7-ketocholesterol led to mutagenesis in mammalian cells remains largely unexplored. Here, we investigated the major role of lipid peroxidation in the genotoxic response to 7-ketocholesterol in chinese hamster ovary (CHO) cells. The results showed that 7-ketocholesterol induced gene mutation and DNA double-strand breaks (DSBs) in concentration- and time-dependent manner. After CHO cells were treated with 25 µM 7-ketocholesterol for 48 h, the mutation frequency at hprt gene loci and the level of γ-H2AX protein were both significantly increased. Exposure to 7-ketocholesterol resulted in a concentration-dependent increase in the apoptotic rate and the protein expression of cleaved caspase-3 and -7 in CHO cells. Moreover, a significant increase of superoxide dismutase (SOD) activity and content of malondialdehyde (MDA) was also observed. Using a inhibitor of lipid peroxidation (butylated hydroxytoluene), it was found to remarkably inhibit the genotoxicity and MDA levels caused by 7-ketocholesterol. These findings indicated that lipid peroxidation was involved in the mutagenic process of 7-ketocholesterol in CHO cells.

Author Correction: PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Interaction of TPPP3 with VDAC1 Promotes Endothelial Injury through Activation of Reactive Oxygen Species.

Endothelial injury plays a critical role in the pathogenesis of cardiovascular disorders and metabolic-associated vascular complications which are the leading cause of death worldwide. However, the mechanism underlying endothelial dysfunction is not completely understood. The study is aimed at investigating the role of tubulin polymerization-promoting protein family member 3 (TPPP3) in palmitic acid- (PA-) induced endothelial injury. The effect of TPPP3 on human umbilical vein endothelial cells (HUVECs) was determined by evaluating apoptosis, tube formation, and reactive oxygen species (ROS) production. TPPP3 silencing inhibited PA overload-induced apoptosis and production of ROS, along with the alteration of apoptosis-related key proteins such as BCL-2 and Bax. Mechanically, voltage-dependent anion channel 1 (VDAC1) was identified as a novel functional binding partner of TPPP3, and TPPP3 promoted VDAC1 protein stability and its activity. Further studies indicated that TPPP3 could promote apoptosis, ROS production, tube formation, and proapoptotic protein expression and reduce antiapoptotic protein expression through increasing VDAC1 expression under mildly elevated levels of PA. Collectively, these results demonstrated that TPPP3 could promote PA-induced oxidative damage in HUVECs via a VDAC1-dependent pathway, suggesting that TPPP3 might be considered as a potential therapeutic target in vascular disease.

Corrigendum: MicroRNA-138-5p Suppresses Non-small Cell Lung Cancer Cells by Targeting PD-L1/PD-1 to Regulate Tumor Microenvironment.

[This corrects the article DOI: 10.3389/fcell.2020.00540.].

PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis.

Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains unclear. PD-L1 has been detected in the nucleus, with unknown function. Here we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C (GSDMC) gene. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8 and GSDMC are required for macrophage-derived TNFα-induced tumour necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/caspase-8 mediates a non-canonical pyroptosis pathway in cancer cells, causing tumour necrosis.

Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment.

Immune checkpoint inhibitors (ICIs) targeting immune checkpoint proteins, such as CTLA-4 and PD-1/PD-L1, have demonstrated remarkable and durable clinical responses in various cancer types. However, a considerable number of patients receiving ICIs eventually experience a relapse due to diverse resistance mechanisms. As a result, there have been increasing research efforts to elucidate the molecular mechanisms behind resistance to ICIs and improve patient outcomes. There is growing evidence that the dysregulated metabolic activity of tumor cells generates an immunosuppressive tumor microenvironment (TME) that orchestrates an impaired anti-tumor immune response. Notably, the immunosuppressive TME is characterized by nutrient shortage, hypoxia, an acidic extracellular milieu, and abundant immunosuppressive molecules. A detailed understanding of the TME remains a major challenge in mounting a more effective anti-tumor immune response. Herein, we discuss how tumor cells reprogram metabolism to modulate a pro-tumor TME, driving disease progression and immune evasion; in particular, we highlight potential approaches to target metabolic vulnerabilities in the context of anti-tumor immunotherapy.