Targeting amino acid metabolism in cancer growth and anti-tumor immune response

Recent advances in amino acid metabolism have revealed that targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. There are currently several drugs in clinical trials that specifically target amino acid metabolic pathways in tumor cells. In the context of the tumor microenvironment,however,tumor cells form metabolic relationships with immune cells,and they oftencompete for common nutrients. Many tumors evolved to escape immune surveillance by taking advantage of their metabolic flexibility and redirecting nutrients for their own advantage. This review outlines the most recent advances in targeting amino acid metabolic pathways in cancer therapy while giving consideration to the impact these pathways may have on the anti-tumor immune response.

Anti-tumor Immune Response Mediated by Newcastle Disease Virus HN Gene

Hemagglutinin-neuramidinase（HN） is one of the most important surface structure proteins of the Newcastle disease virus（NDV）. HN not only mediates receptor recognition but also possesses neuraminidase（NA） activity, which gives it the ability to cleave a component of those receptors, NAcneu. Previous studies have demonstrated that HN has interesting anti-neoplastic and immune-stimulating properties in mammalian species, including humans. To explore the application of the HN gene in cancer gene therapy, we constructed a Lewis lung carcinoma（LLC） solid tumor model using C57BL/6 mice. Mice were injected intratumorally with the recombinant adenovirus expressing HN gene（Ad-HN）, and the effect of HN was explored by natural killer cell activity assay, cytotoxic lymphocyte activity assay, T cell subtype evaluation, and Th1/Th2 cytokines analysis. The results demonstrate that HN not only can elicit clonal expansion of both CD4＋ and CD8＋ T cell populations and cytotoxic T lymphocyte（CTL） and killer cell response, but also skews the immune response toward Th1. Thus, vaccination with Ad-HN may be a potential strategy for cancer gene therapy.

Investigation on the Effects of Soluble Programmed Death-1 (sPD-1) Enhancing Anti-tumor Immune Response

Summary: By using semi-quantitative RT-PCR method, it was found that PD-L1 mRNA but not PD-L2 mRNA was expressed in H22 hepatoma cells and both PD-L1 and PD-L2 mRNAs were expressed in tumor tissues of tumor-bearing mice and upregulated as compared with muscle tissues in normal mice and H22 hepatoma cells. PD-L1 and PD-L2 were also expressed on the surface of the activated T cells. The soluble recombinant sPD-1 expressed from the constructed eukaryotic expression vector could enhance the lysis of tumor cells by lymphocytes stimulated specifically with antigen. The expresssion of sPD-1 by local gene therapy on the inoculation site of H22 hepatoma cells could inhibit the growth of tumor. The results of this study indicate that expression of soluble receptor of negative costimulatory molecules could reduce the inhibitory effect on T cells in tumor microenvironment and enhance the cytotoxicity of T cells on tumor cells. This possibly provides a new method of improving efficacy of tumor gene therapy.

Immunization with autologous T cells enhances in vivo anti-tumor immune responses accompanied by up-regulation of GADD45β

Immunization with inactivated autoreactive T cells may induce idiotype anti-idiotypic reactions to deplete autoreac-tire T cells,which are involved in autoimmune diseases.However,it is unknown whether attenuated activated healthyautologous T-cell immunization could increase anti-tumor immune responses.To this end,C57B1/6 mice were immunizedwith attenuated activated autologous T cells.The splenocytes from immunized mice showed a higher proliferative abil-ity than that from naive mice.The special phenotype analysis showed that there were more CDS+T cells and CD62L+T cells in immunized mice after 24 h of culture with 10% fetal calf serum complete medium in vitro(P<0.01).Theseresults demonstrated that this immunization may activate T cells in vivo.Furthermore,the splenocytes from immunizedmice revealed resistance to activation-induced cell death(AICD)in vitro.To further study the relative genes that areresponsible for the higher proliferation and resistance to AICD,the expression of Fas/Fas ligand(FasL)and GADD45βwas measured by real-time PCR.The results indicated that GADD45β transcription was higher in the splenocytes fromimmunized mice than that in the naive mice.In addition,the Fas expression showed a parallel higher,but FasL did notchange obviously.To investigate the biologic functions induced by immunization in vivo,a tumor model was establishedby EL-4 tumor cell inoculation in C57/B1 mice.Mice receiving autologous T-cell immunization had significantly inhibitedtumor growth in vivo(P<0.01).This study implicated that immunization with attenuated activated autologous T cellsenhances anti-tumor immune responses that participate in tumor growth inhibition.

Heat-shocked tumor cell lysate-pulsed dendritic cells induce effective anti-tumor immune response in vivo

瞄准：学习震惊热的肿瘤房间是否能提高肿瘤房间的效果在唤起反肿瘤免疫者反应的搏动 lysate 的树枝状的房间(DC ) 在活体内。方法：老鼠无差别的结肠癌房间(CT-26 ) 为 1 h 然后结冰融化在 42 度摄氏被加热。骨头导出髓的 DC 与震惊热的 CT-26 房间溶解产物(HSCT-26 DC ) 搏动了被招募使 syngeneic 免疫天真的 BALB/c 老鼠。肿瘤的细胞毒素的活动在老鼠怒气的特定的细胞毒素的 T 淋巴细胞(CTL ) 被 IFN-enzyme-linked 免疫点(ELISpot ) 和 LDH 版本试金评估。在老鼠结肠癌的 DC 建模的 HSCT-26 导致的免疫 prophylactic 效果与单个 CT-26 房间导致的那些相比肿瘤体积，腹转移和老鼠的生存时间上的搏动 lysate 的 DC (CT-26 DC ) 。结果：对待热的 CT-26 房间显示出更高的 hsp70 蛋白质表情。震惊热的 CT-26 房间溶解产物 pulsing 提高了骨头的 co-stimulatory 和 MHC-II 分子表示导出髓的 DC 以及 interleukin-12 p70 分泌物。HSCT-26 DC 导致的 IFN-gamma secreting CTL 被 CT-26 DC (P=0.002 ) 显著地多于那些导致。以前的 CTL 的特定的细胞毒素的活动在 10:1， 20:1，和 40:1 的连续 E/T 比率比后者 CTL 的家高。尽管他们之间没有统计差别，鼠标结肠癌模型比 CT-26 DC，种痘在肿瘤体积上组织证明种痘组织的 HSCT-26 DC 的肿瘤卷小(24 mm3 对 8 mm3， P=0.480 ) 。与 HSCT-26 DC 使免疫的老鼠的中部的生存时间比与 CT-26 DC 使免疫的那些的长(57 d 对 43 d， P=0.0384 ) 。结论：震惊热的肿瘤房间搏动 lysate 的 DC 能有效地唤起反肿瘤免疫者反应在活体内并且用作一支新奇基于 DC 的肿瘤疫苗。

Apoptotic B16-F1 Cells Coated with Recombinant Calreticulin Mediated Anti-tumor Immune Response in Mice

Objective： To investigate the recombinant calreticulin （rCRT） mediated antitumor immune response. Methods： Cell proliferation was determined by MTT method, apoptosis was evaluated by DNA fragmentation and CRT expression and cell localization were assayed by western blotting, QT-RT-PCR and immunofluorescence assays. The mouse melanoma cell line B16-F1 was treated with polyamine analogue BENS to induce apoptosis and incubated with rCRT to get rCRT coated on the membrane, and then the cells were used to immune BALB/c mice as a cell-antigen. Immunized animals were rechallenged by live B16-F1 cells and then tumor generation ratio and the lactate dehydrogenase release assay were used to evaluate antitumor effects of rCRT-mediated immunity. Results： BENS induced apoptosis of B16-F1 cells without the redistribution of CRT within the cells. When B16-F1 cells coated with rCRT were used as cell-antigen to inoculate the animals, the mice obtained the ability in inhibiting proliferation of homologous tumor cells in vivo. Comparing with the positive control group, the splenocytes from those inoculated mice have an obvious enhancement on their cytolytic effects specifically against B16-F1 cells. Conclusion： rCRT coated on the cell surface can enhance immunogenicity of apoptotic tumor cells and mediated effective anti-tumor immunoresponse in mice.

Effect of postoperative early enteral nutrition support on anti-tumor immune response and inflammatory response process in the elderly patients with esophageal cancer

Objective: To explore the effect of postoperative early enteral nutrition support on anti-tumor immune response and inflammatory response process in the elderly patients with esophageal cancer. Methods: A total of 110 cases of elderly patients with esophageal cancer who underwent radical operation in this hospital between January 2015 and December 2017 were divided into the parenteral nutrition group (n=57) who received parenteral nutrition support and the enteral nutrition group (n=53) who received enteral nutrition support according to the postoperative nutrition intervention methods. The differences in anti-tumor immune response and inflammatory response degree were compared between the two groups of patients immediately after the patients returned to the ward (T0), 48h after nutritional support (T1) and 72h after nutritional support (T2). Results: At T0, there was no statistically significant difference in the contents of Th1/Th2 immune response and Th17/Treg immune response indexes as well as inflammatory mediators in serum between the two groups of patients. At T1 and T2, serum Th1 cytokines IFN-γ and IL-12 contents of enteral nutrition group were higher than those of parenteral nutrition group whereas Th2 cytokines IL-4 and IL-13 contents were lower than those of parenteral nutrition group;serum contents of Th17 cytokines IL-6 and IL-17 as well as Treg cytokines TGF-β and IL-10 were lower than those of parenteral nutrition group;serum inflammatory mediators hs-CRP, PGE and HMGB1 contents were lower than those of parenteral nutrition group. Conclusion: Postoperative early enteral nutrition support can effectively regulate the Th1/Th2 and Th17/Treg immune response balance and inhibit the systemic inflammatory response in elderly patients with esophageal cancer.

Effects of different chemotherapy regimens before radical operation for lung cancer on cancer cell growth and anti-tumor immune response

Objective:To investigate the effects of different chemotherapy regimens before radical operation for lung cancer on cancer cell growth and antitumor immune response.Methods: A total of 180 patients with primary lung cancer who underwent surgery in this hospital between February 2013 and August 2017 were divided into the cisplatin group (n=93) who received cisplatin & paclitaxel chemotherapy and the lobaplatin group (n=87) who received lobaplatin & paclitaxel chemotherapy according to different preoperative neoadjuvant chemotherapy regimens. The differences among the expression of proliferation genes and apoptosis genes in tumor tissues as well as the contents of Th1/Th2 cytokines in serum were compared between the two groups.Results: Proliferation genes DDX17, GPx1, MACC1, RACK1 and SIRT1 mRNA expression levels in tumor tissue of lobaplatin group were lower than those of cisplatin group whereas LRRC3B mRNA expression level was higher than that of cisplatin group;apoptosis gene Fas, FasL and Caspase-3 mRNA expression levels were higher than those of cisplatin group whereas Survivin and Bcl-2 mRNA expression levels were lower than those of cisplatin group;serum Th1 cytokines IFN-γ and IL-12 contents were higher than those of cisplatin group whereas Th2 cytokines IL-5 and IL-10 contents were lower than those of cisplatin group.Conclusion: Lobaplatin chemotherapy before radical operation for lung cancer is more effective than cisplatin chemotherapy to inhibit the proliferation activity and enhance the apoptosis activity of lung cancer cells and optimize the anti-tumor immune response.

Effect of negative emotion on tumor load and anti-tumor immune response in bladder cancer infusion chemotherapyn

Objective: To study the effect of negative emotion on tumor load and anti-tumor immune response in bladder cancer infusion chemotherapy. Methods: Patients with advanced bladder cancer who received bladder infusion chemotherapy in the First People's Hospital of Ziyang between May 2014 and December 2016 were selected and divided into the control group without negative emotions, the anxiety group with anxiety, the depression group with depression and the anxiety depression group with both anxiety and depression according to the assessment results of HAMA scale and HAMD scale. The contents of tumor markers in serum, the contents of immune cells in peripheral blood and the expression of apoptosis genes in urine were detected during chemotherapy. Results: DKK-1, DKK-3, OPN and CYFRA21-1 contents in serum as well as PD-1+CD4+T cell, PD-1+CD8+T cell and B7-H1+CD11c+DC cell contents in peripheral blood of anxiety group, depression group and anxiety depression group were significantly higher than those of control group while DAP2IP, Fas, FasL, Caspase-8 and PTEN protein expression in urine were significantly lower than those of control group, and DKK-1, DKK-3, OPN and CYFRA21-1 contents in serum as well as PD-1+CD4+T cell, PD-1+CD8+T cell and B7-H1+CD11c+DC cell contents in peripheral blood of anxiety depression group were significantly higher than those of anxiety group and depression group while DAP2IP, Fas, FasL, Caspase-8 and PTEN protein expression in urine were significantly lower than those of anxiety group and depression group. Conclusion: The anxiety and depression in bladder cancer infusion chemotherapy can suppress the expression of apoptosis genes and the anti-tumor immune response to lead to more vigorous proliferation of cancer cells.

Effect of dietary fiber enteral nutrition on inflammatory response and anti-tumor immune response after colorectal cancer surgery

Objective: To study the effect of dietary fiber enteral nutrition on inflammatory response and anti-tumor immune response after colorectal cancer surgery. Methods: A total of 162 patients who underwent radical operation for colorectal cancer in West China Hospital, Sichuan University between March 2015 and August 2017 were selected as the research subjects and randomly divided into the dietary fiber group who accepted dietary fiber enteral nutrition intervention and the control group who accepted conventional nutrition intervention. The number of intestinal flora was determined before surgery and at the first defecation after surgery;the inflammatory response indexes and immune response indexes were measured before surgery as well as 3 d and 5 d after surgery. Results: At the first defecation after surgery, the bifidobacteria, lactobacillus, Escherichia coli and enterococcus contents in the feces of both groups were lower than those before surgery, and the bifidobacterium and lactobacillus contents in feces of dietary fiber group were higher than those of control group whereas Escherichia coli and enterococcus contents were lower than those of control group;3 d and 5 d after surgery, NF-κB, IL-1, TNF-α and IL-8 contents in serum as well as Treg, Th17, Th22, TGF-β, IL-17 and IL-22 contents in peripheral blood of both groups of patients were significantly higher than those before surgery, and NF-κB, IL-1, TNF-α and IL-8 contents in serum as well as Treg, Th17, Th22, TGF-β, IL-17 and IL-22 contents in peripheral blood of dietary fiber group were lower than those of control group. Conclusion: The dietary fiber enteral nutrition intervention after colorectal cancer surgery can inhibit the inflammatory response and improve the anti-tumor immune response.

CD146 Bound to LCK Promotes T Cell Activation and Anti-tumor Immune Response in Mice

As an essential component of the immune system,T lymphocytes play an indispensable role in fighting bacteria or viruses and killing tumor cells.T cell activation undergoes an orderly and complex process that critically relies on T cell antigen receptor(TCR)signaling,which requires an orchestrated interplay of receptors,receptor-associated factors,kinases,and transcription factors,together termed TCR signalosome.Although the intracellular signaling cascade has been extensively studied,exactly how membrane TCR activation leads to intracellular signaling has remained elusive.

Changes of serum endocrine hormone levels in patients with cancer-related fatigue and their correlation with anti-tumor immune response and tumor load

Objective: To study the changes of serum endocrine hormone levels in patients with cancer-related fatigue (CRF) and their correlation with anti-tumor immune response and tumor load. Methods: A total of 137 patients who were diagnosed with primary lung cancer in West China Hospital, Sichuan University between June 2014 and November 2016 were selected and then divided into CRF group and control group according to their self-reported symptoms, serum was collected to determine the levels of endocrine hormones and tumor markers, and peripheral blood was collected to detect the levels of immune cells. Results: Serum ACTH and TSH levels of CRF group were significantly higher than those of control group while Cor, FT3 and FT4 levels were significantly lower than those of control group;peripheral blood CD11b+CD15-CD33+CD14+M-MDSC, CD11b+CD15-CD33+CD14-G-MDSC, CD4+CD25+CD127lowTreg and CD19+CD5+CD1d+Breg levels as well as serum CEA, Cyfra21-1, SCC-Ag, HE4, GDF-15 and PCNA levels of CRF group were significantly higher than those of control group, positively correlated with serum ACTH and TSH levels, and negatively correlated with Cor, FT3 and FT4 levels. Conclusion: The changes of thyroid hormone and adrenal cortical hormone levels in patients with cancer-related fatigue are closely related to the inhibited anti-tumor immune response and increased tumor load.

Effect of enteral immunonutrition after radical surgery for esophageal carcinoma on anti-tumor immune response and intestinal mucosal barrier function

Objective:To study the effect of enteral immunonutrition after radical surgery for esophageal carcinoma on anti-tumor immune response and intestinal mucosal barrier function.Methods:A total of102 patients who received radical surgery for esophageal carcinoma in our hospital between May 2013 and December 2016 were selected and randomly divided into observation group and control group who received postoperative enteral immunonutrition and routine enteral nutrition respectively. 1 d before operation as well as 1 d and 7 d after operation, peripheral blood immune cell marker expression and serum intestinal mucosal barrier injury marker levels were detected.Results:1 d after operation, peripheral blood T-bet, NKG2D, NKp30, NKp44 and NKp46 fluorescence intensity of both groups of patients were significantly lower than those 1d before operation while peripheral blood GATA-3 and Foxp3 fluorescence intensity as well as serum DAO, Occludin, ZO-1 and claudin-1 levels were significantly higher than those 1d before operation;peripheral blood T-bet, NKG2D, NKp30, NKp44 and NKp46 fluorescence intensity of observation group 7 d after operation were significantly higher than those 1 d after operation while peripheral blood GATA-3 and Foxp3 fluorescence intensity as well as serum DAO, Occludin, ZO-1 and claudin-1 levels were significantly lower than those 1 d after operation;peripheral blood T-bet, GATA-3, Foxp3, NKG2D, NKp30, NKp44 and NKp46 fluorescence intensity of control group 7 d after operation were not significant different from those 1 d after operation, and serum DAO, Occludin, ZO-1 and claudin-1 levels were significantly lower than those 1d after operation.Conclusion: Enteral immunonutrition after radical surgery for esophageal carcinoma can enhance the anti-tumor immune response and improve the intestinal mucosal barrier function.

Mitochondria-targeted atovaquone promotes anti-lung cancer immunity by reshaping tumor microenvironment and enhancing energy metabolism of anti-tumor immune cells

Dear Editor,Atovaquone(ATO),a mitochondrial inhibitor,has anti-cancer effects[1].Based on ATO,we developed mitochondria-targeted atovaquone(Mito-ATO)that had even stronger anti-tumor efficacy than ATO[2].We syn-thesized Mito-ATO by attaching the bulky triphenylphos-phonium(TPP)group to ATO via a ten-carbon alkyl chain(Supplementary file of methods;Supplementary Figure S1).

Immune regulation of the gut-brain axis and lung-brain axis involved in ischemic stroke

Local ischemia often causes a series of inflammatory reactions when both brain immune cells and the peripheral immune response are activated.In the human body,the gut and lung are regarded as the key reactional targets that are initiated by brain ischemic attacks.Mucosal microorganisms play an important role in immune regulation and metabolism and affect blood-brain barrier permeability.In addition to the relationship between peripheral organs and central areas and the intestine and lung also interact among each other.Here,we review the molecular and cellular immune mechanisms involved in the pathways of inflammation across the gut-brain axis and lung-brain axis.We found that abnormal intestinal flora,the intestinal microenvironment,lung infection,chronic diseases,and mechanical ventilation can worsen the outcome of ischemic stroke.This review also introduces the influence of the brain on the gut and lungs after stroke,highlighting the bidirectional feedback effect among the gut,lungs,and brain.

Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina

Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.

Spatiotemporal transformable nano-assembly for on-demand drug delivery to enhance anti-tumor immunotherapy

Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy,but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration.Herein,we designed a cancer-associated fibroblasts(CAFs)triggered structure-transformable nano-assembly(HSD-P@V),which can directionally deliver valsartan(Val,CAFs regulator)and doxorubicin(DOX,senescence inducer)to the specific targets.In detail,DOX is conjugated with hyaluronic acid(HA)via diselenide bonds(Se-Se)to form HSD micelles,while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer,which is coated on Val nanocrystals(VNs)surface for improving the stability and achieving responsive release.Once arriving at tumor microenvironment and touching CAFs,HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment.VNs can degrade the extracellularmatrix,leading to the enhanced penetration of HSD.HSD targets tumor cells,releases DOX to induce senescence,and recruits effector immune cells.Furthermore,senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy.In vitro and in vivo results show that the nanoassembly remarkably inhibits tumor growth as well as lungmetastasis,and extends tumorbearing mice survival.This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.

DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation

Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Immune checkpoint inhibitor-associated gastritis:Patterns and management

Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the cessation of ICIs.Although irAE gastritis is rarely reported,it may lead to serious complications such as gastrorrhagia.Furthermore,irAE gastritis is often difficult to identify early due to its diverse symptoms.Although steroid hormones and immunosuppressants are commonly used to reverse irAEs,the best regimen and dosage for irAE gastritis remains uncertain.In addition,the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered.In this editorial,strategies such as early identification,pathological diagnosis,mana-gement interventions,and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.

Immune consequences of exercise in hypoxia:A narrative review

Immune outcomes are key mediators of many health benefits of exercise and are determined by exercise type,dose(frequency/duration,intensity),and individual characteristics.Similarly,reduced availability of ambient oxygen(hypoxia)modulates immune functions depending on the hypoxic dose and the individual capacity to respond to hypoxia.How combined exercise and hypoxia(e.g.,high-altitude training)sculpts immune responses is not well understood,although such combinations are becoming increasingly popular.Therefore,in this paper,we summarize the impact on immune responses of exercise and of hypoxia,both independently and together,with a focus on specialized cells in the innate and adaptive immune system.We review the regulation of the immune system by tissue oxygen levels and the overlapping and distinct immune responses related to exercise and hypoxia,then we discuss how they may be modulated by nutritional strategies.Mitochondrial,antioxidant,and anti-inflammatory mechanisms underlie many of the adaptations that can lead to improved cellular metabolism,resilience,and overall immune functions by regulating the survival,differentiation,activation,and migration of immune cells.This review shows that exercise and hypoxia can impair or complement/synergize with each other while regulating immune system functions.Appropriate acclimatization,training,and nutritional strategies can be used to avoid risks and tap into the synergistic potentials of the poorly studied immune consequences of exercising in a hypoxic state.